Process of making an iontophoresis electrode

ABSTRACT

A process for making a medical electrode component that includes dispersing a pH buffering agent within a first absorbent material that is capable of absorbing electrolytic solution or applying the pH buffering agent as a coating on a substantially planar surface of the first absorbent material, forming a first web having first and second surfaces from the first absorbent material, forming a second web from a second absorbent material that is capable of absorbing electrolytic solution, cutting through the first web to form a first web portion having a first surface and a second surface, cutting through the second web to form a second web portion having a first surface and a second surface, and securing the second surface of the first web portion and the first surface of the second web portion in contact to secure the first web portion and the second web portion in layered relation.

BACKGROUND OF THE INVENTION

The present invention generally relates to an apparatus fortransdermally delivering medicament ions derived from ionic substances,such as drugs or other therapeutic chemicals, into a body. Moreparticularly, the present invention relates to an apparatus foriontophoretically introducing medicament ions into the body.

Iontophoresis may be generally described as a method of transdermallyintroducing medicament ions into a body. The iontophoresis processutilizes current developed by an electric field to drive medicament ionsthrough the skin, or other biological surface, and into the body. Theiontophoresis process has been found to be particularly useful intransdermal administration of medicament ions, such as charged organicmedications and therapeutic metal ions.

Iontophoresis permits introduction of medicament ions directly into apatient's tissues and blood stream without the need for a needle-basedinjection, which typically causes pain and may create a risk ofinfection. Iontophoretic delivery of medicament ions also avoidspremature metabolism of medicament ions that typically occurs when drugsare taken orally. Premature metabolism is of concern because medicamentions derived from drugs that are taken orally are absorbed into theblood stream from the digestive system. The blood containing themedicament ions then percolates through the liver, where the medicamentions may be prematurely metabolized, before the medicament ions arriveat the target tissue. Thus, a substantial amount of the medicament ionsderived from an orally administered drug may be metabolicallyinactivated before the medicament ions have a chance topharmacologically act in the body.

A typical iontophoresis device includes two electrodes. One of theelectrodes is often characterized as an "active" electrode, and theother electrode is often characterized as a "return" electrode. Also,one of the electrodes is a positively charged anode and the otherelectrode is a negatively charged cathode. Both electrodes are inintimate electrical contact with the skin or other biological surface ofthe body, which may be a human body or another type of body, such as ananimal body. Application of electric current to the active electrodedrives the medicament ion, such as the charged organic medication, fromthe active electrode into the body. The other electrode, the returnelectrode, closes the electrical circuit to permit current flow throughthe active electrode and through the body.

In some cases, medicament ions may be delivered to the body from bothelectrodes of the iontophoresis system. In such cases, a first electrodeis the active electrode for a first medicament ion that is deliveredfrom the first electrode, and a second electrode is the return electrodewith respect to the first medicament ion. Similarly, the secondelectrode is the active electrode for a second medicament ion that isdelivered from the second electrode, and the first electrode is thereturn electrode with respect to the second medicament ion. The firstand second medicament ions are typically different in polarity and inchemical structure from each other.

Though iontophoresis system technology has realized several advances,numerous problems remain to be solved and many opportunities forenhancing performance remain. The process of iontophoretic drug deliverymay be accomplished using very simple electrodes. However, the use ofmore sophisticated electrode configurations is needed to solve problemsthat are not addressed by simple electrode systems and to realizeenhanced performance characteristics. Examples of some suggestedapproaches for optimizing iontophoresis systems are included in U.S.Pat. Nos. 4,731,049 to Parsi; 4,915,685 to Petelenz et al.; and5,302,172 to Sage, Jr. et al. The Parsi patent suggests a change in theiontophoresis systems that is said to increase the types of drugsdeliverable by iontophoresis systems. The Petelenz patent suggestschanges that are said to enhance the proportional relationship betweenthe amount of medicament ions administered and current flow. Finally,the Sage, Jr. patent discloses the use of vasodilators in iontophoresisas a means of enhancing delivery of an active agent that is deliveredalong with vasodilator.

Despite the many advances in iontophoresis technology, a series ofproblems remain that relate to electrolysis of water in iontophoresissystem electrodes. As an example, current passing through the electrodesof an iontophoresis system typically cause electrolysis of water in theelectrodes. In the anode, the electrolysis reaction proceeds as follows:

    2H.sub.2 O→O.sub.2 +4H.sup.+ +4.sub.e.sup.-.

In the cathode, the electrolysis reaction proceeds as follows:

    2H.sub.2 O+2.sub.e.sup.- →H.sub.2 +2OH.sup.-.

Since an operational iontophoresis system includes both an anode and acathode, both hydrogen ions (H⁺) and hydroxide ions (OH⁻) are producedif electrolysis of water occurs during system operation. Absentbuffering of the electrolysis products, the hydrogen ion concentrationwill increase at the anode and the hydroxide ion concentration willincrease at the cathode.

Hydrogen ion and hydroxide ion accumulation in the electrodes ofiontophoresis systems is problematic for a variety of reasons. Forexample, the increased hydrogen ion concentration shifts the pH downwardat the anode, and the increased hydroxide ion concentration shifts thepH upward at the cathode. The pH shift typically causes at least minorskin irritation and can cause severe burning of a patient's skin, ifleft uncontrolled. Also, the pH shift can change the activity of themedicament ion(s) being delivered by the electrode, can significantlyreduce the rate of medicament ion delivery by the electrode, and caneven degrade the physical properties of the electrode components.

One technique for controlling the pH shift involves the introduction ofone or more buffering species into the iontophoretic electrodes. Thebuffering species may be in solution with the solution of the medicamention to be delivered in the medicament delivery portion of the electrode.However, when the buffering species is in solution with the medicamention in the medicament delivery portion of the electrode, experience hasshown that the buffering species and derivatives of the bufferingspecies undesirably compete with medicament ions for delivery to thetarget body.

Another technique for incorporating buffering species in iontophoresiselectrodes is disclosed in U.S. Pat. No. 4,973,303 to Johnson et al.Though there are benefits to the technique disclosed in the Johnsonpatent, it has been found that the amount of ion-exchange functionalityincluded in the buffer of the Johnson electrode cannot be accuratelycontrolled. Furthermore, the Johnson technique uses several times morebuffering agent than is chemically required to buffer water electrolysisproducts.

Though many advances in iontophoretic electrode design and operationhave been realized, challenges requiring solutions remain. For example,less complicated and more accurate techniques are needed for controllingthe amount of buffering species included in iontophoresis electrodes.Also, opportunities remain for enhancing the rate of medicament iondelivery by iontophoresis electrodes. Finally, opportunities remain forsimplifying electrode manufacturing techniques and automating theiontophoresis electrode manufacture.

SUMMARY OF THE INVENTION

The present invention includes a process for making a medical electrodecomponent that includes dispersing a pH buffering agent within a firstabsorbent material that is capable of absorbing electrolytic solution orapplying the pH buffering agent as a coating on a substantially planarsurface of the first absorbent material, forming a first web havingfirst and second surfaces from the first absorbent material, forming asecond web from a second absorbent material that is capable of absorbingelectrolytic solution, cutting through the first web to form a first webportion having a first surface and a second surface, cutting through thesecond web to form a second web portion having a first surface and asecond surface, and securing the second surface of the first web portionand the first surface of the second web portion in contact to secure thefirst web portion and the second web portion in layered relation.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a sectional view of a pH buffered electrode of the presentinvention.

FIG. 2 is a sectional view of another pH buffered electrode of thepresent invention.

FIG. 3 is a sectional view of another pH buffered electrode of thepresent invention.

FIG. 4 is a schematic view of an apparatus for manufacturing the pHbuffered electrode of the present invention.

FIG. 5 is a schematic view of another apparatus for manufacturing the pHbuffered electrode of the present invention.

FIG. 6 is a schematic view of another apparatus for manufacturing the pHbuffered electrode of the present invention.

FIG. 7 is a schematic view of another apparatus for manufacturing the pHbuffered electrode of the present invention.

FIG. 8 is a graphical representation of the amount of buffer suspensionincorporated in a buffer component of the present invention versus theweight ratio of glycerin to buffering resin in the buffer suspension.

FIG. 9 is a graphical representation of the amount of buffer suspensionincorporated in a buffer component of the present invention, per gram offoam in the buffer component, versus the weight ratio of glycerin tobuffering resin in the buffer suspension.

FIG. 10 is a graphical representation of the amount of buffering resinincorporated in a buffer component of the present invention, per gram offoam in the buffer component, versus the weight ratio of glycerin tobuffering resin in the buffer suspension.

FIG. 11 is a schematic view of an apparatus for simulating iontophoresisusing various pH buffered electrodes.

FIG. 12 is a graphical representation of the cumulative amount ofdexamethasone phosphate delivered by various pH buffered electrodesversus the charge applied to the electrodes.

FIG. 13 is a graphical representation of the cumulative amount ofdexamethasone phosphate delivered by various pH buffered electrodes, perunit effective delivery area of the electrodes, versus time of electrodeoperation.

FIG. 14 is a graphical representation of the cumulative amount ofprotonated lidocaine delivered by various pH buffered electrodes versusthe charge applied to the electrodes.

FIG. 15 is a graphical representation of the cumulative amount ofprotonated lidocaine delivered by various pH buffered electrodes, perunit effective delivery area of the electrodes, versus time of electrodeoperation.

FIG. 16 is a graphical representation of the cumulative amount ofminoxidil ions delivered by various pH buffered electrodes versus thecharge applied to the electrodes.

FIG. 17 is a graphical representation of the cumulative amount ofminoxidil ions delivered by various pH buffered electrodes, per uniteffective delivery area of the electrodes, versus time of electrodeoperation.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

An iontophoresis electrode of the present invention for deliveringmedicament ions to a body is generally depicted at 10 in FIG. 1. Theelectrode 10 includes a medicament delivery component 12 and a buffercomponent 14. The buffer component 14 is located adjacent to and indirect contact with the medicament delivery component 12. pH bufferingagent is preferably dispersed uniformly throughout the buffer component14. However, a buffer coating that includes the pH buffering agent mayalternatively be applied to an outer surface of the component 14. Theelectrode 10 further includes a conductive component 16 that is locatedadjacent to and in contact with the buffer component 14. The buffercomponent 14 is thus located between the medicament delivery component12 and the conductive component 16.

The electrode 10 additionally includes a conductive tab or terminal 18,such as a conductive snap connector, that is attached in electricalcommunication to the conductive component 16. The terminal 18 couplesthe electrode 10 to a source of electrical power (not shown), such as asource of direct current. The electrode 10 also incorporates an adhesivecovering 20 that serves as a structural support component of theelectrode 10 and is also useful for securing the electrode 10 to theskin (not shown).

The medicament delivery component 12 and the buffer component 14 areeach made of absorbent material that is capable of quickly absorbing anelectrolytic solution and maintaining the electrolytic solution as aconfluent liquid phase within the absorbent material. The absorbentmaterial of the components 12, 14 should be capable of being fullywetted by the electrolytic solution. The electrolytic solution includesconductive ions and a solvent that is capable of maintaining theconductive ions in solution. Some examples of the solvent include (1)water and (2) a mixture of water and an organic liquid such as analcohol, depending upon the solubility of the conductive ions. Theelectrolytic solution may either include medicament ions andcomplimentary ions of the medicament ions or may be free of medicamentions and the complimentary ions.

The absorbent material of the buffer component 14 preferablyincorporates pH buffering agent that is distributed or dispersed insubstantially uniform fashion throughout the absorbent material. The pHbuffering agent may be an ion exchange substance, such as ion-exchangeresin, that is capable of buffering water electrolysis products producedduring operation of the electrode 10 to maintain the pH of theelectrolytic solution within a range of about 4 to about 8 standard pHunits. Alternatively, the absorbent material of the buffer component 14may include the buffer coating to incorporate the pH buffering agent aspart of the buffer component 14. No matter how the buffer component 14incorporates the pH buffering agent, the pH buffering agent should beimmobilized to prevent, or predominantly prevent, the pH buffering agentfrom interfering with medicament ions that are located in the medicamentdelivery component 12.

A major benefit of the electrode 10 is the opportunity that thestructure of the electrode 10 affords for separating the pH bufferingagent from the medicament delivery component 12. This separation permitssimultaneous medicament ion delivery to the body by the medicamentdelivery component and buffering of water electrolysis products by thepH buffering agent, while avoiding any deleterious impact by the pHbuffering agent on medicament ion delivery by the component 12.

Electrolytic solution that contains medicament ions and complimentaryions of the medicament ions may be held in both the medicament deliverycomponent 12 and the buffer component 14. In the experience of theinventors, the presence of medicament ions and complimentary ions in thebuffer component 14 does not degrade the rate of medicament ion deliveryto the body by the component 12. Medicament ions present in themedicament delivery component 12 are delivered to the body at the samerate, regardless of medicament ions being present or absent in thecomponent 14. Therefore, there is no need for the electrode 10 toinclude any sort of barrier, such as a semi-permeable membrane or an ionexchange membrane, to prevent medicament ion and complimentary ion entryinto the buffer member 14 from the medicament delivery component 12.This absence of any such barrier to medicament ion movement into thebuffer component 14 from the medicament ion delivery component 12simplifies both the structure and the manufacture of the electrode 10.

Though the component 12 and the component 14 are located adjacent toeach other and are in direct contact with each other, there should be adistinct interface 21 or boundary between the absorbent material of thecomponent 12 and the absorbent material of the component 14 to insureadequate separation of the pH buffering agent from the medicamentdelivery component 12. The interface 21 should exist throughout the lifeof the electrode 10 to insure lifetime optimum performance of theelectrode 10. The interface 21 is preferably smooth in nature. Theabsorbent material of the component 12 and the absorbent material of thecomponent 14 should not merge with each other to any degree at theinterface 21 between the components 12, 14, but should instead bedistinct from each other. The smooth nature of the boundary 21 helpsmaintain the components 12, 14 as distinct, separate components thatcooperate with each other through the direct contact.

It is believed that medicament ion delivery by the component 12 willtend to decrease as the pH buffering agent increasingly interferes withmedicament ions that are present in the component 12. Thus, the pHbuffering agent should not be incorporated into the component 12, sinceit is believed that pH buffering agent that is incorporated in thecomponent 12 would at least substantially interfere with medicament ionmovement within the component 12 and with medicament ion delivery by thecomponent 12 to the body. Furthermore, the distinct interface 21 betweenthe component 12 and the component 14 should remain during the life ofthe electrode 10 to minimize interference of the pH buffering agent thatis located in the buffer component 14 with medicament ions that arepresent in, and delivered to the body by, the medicament deliverycomponent 12.

It is believed that pH buffering agent interference with medicament ionmovement and delivery results from electro-migration and diffusionphenomena that arise during iontophoresis. These electro-migration anddiffusion phenomena are believed to arise whenever pH buffering agent islocated between the body and medicament ions to be delivered to thebody. This explains why the pH buffering agent should not be included aspart of the component 12, but should instead be located outside of thecomponent 12 so that the component 12 is located between the body andthe pH buffering agent. At least some of the electro-migration anddiffusion phenomena are also believed to exist whenever medicament ionsand pH buffering agent are located adjacent to each other and at aboutthe same distance from the body. This is why the distinct interface 21,which is preferably smooth, should exist between the component 12 andthe component 14.

Though medicament ions will typically be present in the buffer component14, in addition to the medicament delivery component 12, it is believedthat predominantly all of the medicament ions that are delivered to thebody are delivered by the medicament delivery component 12. That is whythe component 12 is designated as the medicament delivery component 12.It is believed that less than about 10 weight percent, and possibly lessthan about 5 weight percent, of the medicament ions that are deliveredto the body are delivered by the buffer component 14. This discrepancybetween medicament ion delivery by the component 12 versus medicamention delivery by the component 14 is believed due to the interference ofthe pH buffering agent of the component 14 with medicament ions that arelocated in the buffer component 14.

The electrode 10 exhibits greatly improved medicament ion delivery flux,as compared to existing iontophoresis electrodes, despite interferenceof pH buffering agent with medicament ions that are located in thebuffer component 14. The inventive placement of the medicament deliverycomponent 12 between the pH buffering agent and the body effectivelyisolates the pH buffering agent from medicament ions that are located inand are delivered by the component 12. Thus, the delivery flux ofmedicament ions that originate in the medicament delivery component 12is unfettered by the pH buffering agent and is many times greater thanthe delivery flux of medicament ions that originate in the buffercomponent 14. Due to isolation of the pH buffering agent away from thecomponent 12 and the presence of the distinct interface 21 during thelife of the electrode 10, improved medicament delivery flux is thereforeattained by the electrode 10, while retaining the highly desirablebuffering capabilities of the pH buffering agent.

The size and resultant medicament ion capacity of the medicamentdelivery component 12 should compensate for the relatively lowmedicament ion efficiency of the buffer component 14 for deliveringmedicament ions to the component 12 from the component 14. Thiscompensation is needed because the medicament ion delivery efficiencyand rate of the buffer component 14 is substantially lower than themedicament ion delivery efficiency and rate of the component 12,regardless of whether or not the components 12 and 14 are of similarsize and medicament ion holding capacity.

Any substance that is to be iontophoretically delivered to the bodyexists as medicament ions. The electrolytic solution that is included inthe medicament delivery component 12 and the buffer component 14 mayinclude one or more different types of medicament ions. The term"medicament ion" is intended to have the broadest possibleinterpretation to encompass any therapeutically active ionic substancethat is deliverable to a living body to produce a desired beneficialeffect.

The electrode 10 may be used to deliver medicament ions through anybiological surface of any living organism. The term "living organism"includes, but is not limited to, living bodies of human beings andanimals. The term "biological surface", as used herein, is defined toinclude, without limitation, skin, mucosal membranes, nails, bloodvessel walls, and all other biological surfaces of any living organism.It will be appreciated that transportation of medicament ions throughthe biological surface of a living organism may take place in thepresence of an electrical field, such as that produced in aniontophoresis system that includes a pair of electrodes, as well as, asource of electrical current.

All references to "body" in the specification, drawings, and claims ofthis document are to be understood as referring to any living organismthat is capable of being treated by iontophoresis. All references to"skin" in the specification, drawings, and claims of this document areto be understood as referring to any biological surface that is capableof transmitting medicament ions delivered to the biological surface byiontophoresis.

The medicament ions that are present in any electrolytic solution whichis contained in the medicament delivery component 12 and the buffercomponent 14 may be derived from any suitable therapeutically activeionic substance. The ionic substance may be any suitable salt, acid, orbase that dissociates into medicament ions and complimentary ions of themedicament ions in the electrolytic solution. Medications, drugs, andother therapeutic chemicals are some general examples of suitable ionicsubstances.

Some examples of the types of therapeutically active ionic substancesthat may evolve medicament ions in any electrolytic solution of themedicament delivery component 12 and the buffer component 14 include,but are not limited to, a variety of ACE inhibitors, analgesics,anorexics, antiarthritics, antiasthmatic agents, antibiotics,antibodies, antidiabetic agents, antidiarrheals, antidepressants,antihistamines, anti-inflammatory agents, anti-migraine preparations,anti-motion sickness preparations, anti-nauseants, antineoplastics,antiparkinsonism drugs, antipruritics, antipsychotics, antipyretics,antispasmatics, antiviral agents, antiocholinergics, antiarrythmics,antihypertensives, anesthetics, beta-agonists, cardiovascularpreparations, central nervous system stimulants, cough and coldpreparations, decongestants, diagnostics, diuretics, enzymes, hormones,hypnotics, immunosuppressives, muscle relaxants, parasympatholytics,parasympathomimetrics, prostaglandins, proteins, peptides,psychostimulants, sedatives, steroids, sympathomimetrics, tranquilizers,vasodilators, vitamins, and xanthine derivatives.

Some examples of particular ionic substances that may evolve medicamentions in any electrolytic solution of the components 12, 14 include, butare not limited to, morphine sulfate, dexamethasone sodium phosphate,hydrocortisone derivatives, lidocaine hydrochloride, morphinehydrochloride, penicillin, minoxidil tartrate, nitroglycerine, aceticacid, fluoride, and magnesium chloride.

Medicament ions formed on dissociation of ionic substances are desirableions that are intended for delivery into the body via the biologicalsurface. Complimentary ions formed on dissociation of ionic substancesare ions that are not intended for delivery into the body. Aside fromcomplimentary ions, other ions that are not intended for delivery intothe body are subsequently referred to as adverse ions.

Though electrolytic solution included in some iontophoresis systemelectrodes, or electrode components, may not include medicament ions,the electrolytic solution included in these iontophoresis systemelectrodes, or electrode components, should nevertheless includesuitable conductive ions. The conductive ions are needed to supportcurrent flow through the iontophoresis system. The conductive ionsshould be selected so that any conductive ions that are delivered intothe body during iontophoresis do not cause deleterious effects withinthe body. The solvent of the electrolytic solution that is included inany electrode of the iontophoresis system may be any solvent, such aswater, that suitably solubilizes medicament ions or conductive ions thatare included in the electrolytic solution. The solvent of theelectrolytic solution should be selected to avoid any harmful effects tothe body.

An iontophoresis system (not shown) typically includes two electrodes(not shown) that are in electrical contact with the skin of the body.Either or both of the electrodes of the iontophoresis system may havethe structure of the electrode 10. One of the electrodes of theiontophoresis system may be characterized as an "active" electrode ofthe system and the other electrode may be characterized as a "return"electrode of the system. One of the electrodes of the iontophoresissystem also serves as a positively charged anode and the other electrodeis a negatively charged cathode. When one of the electrodes deliversmedicament ions into the body, the electrode delivering the medicamentions is the active electrode and the other electrode, the returnelectrode, completes the electrical circuit through the body between theactive electrode and the return electrode.

When the anode of the iontophoresis system has the structure of theelectrode 10, electrolytic solution is included in both the component 12and the component 14 to support current flow from the terminal 18through the component 16, the component 14, and the component 12, andinto the body. The electrode 10 that serves as the anode may be eitherthe active electrode for delivering medicament ions into the body or maybe the return electrode. When the cathode of the iontophoresis systemhas the structure of the electrode 10, electrolytic solution is includedin both the component 12 and the component 14 to support current flowfrom the body, through the component 12, the component 14, and thecomponent 16, and into the terminal 18. The electrode 10 that serves asthe cathode may be either the active electrode for delivering medicamentions into the body or may be the return electrode.

Also, as explained below, the anode and the cathode that have thestructure of the electrode 10 may each serve as both active and returnelectrodes when medicament ions are delivered from both the anode andthe cathode. Those skilled in the art will readily recognize that in anyelectrode 10 serving only as the return electrode, and not serving atany time during the treatment session as the active electrode, thecomponent 12 is provided only for purposes of helping to complete theelectrical circuit through the body, or for purposes of performingreverse iontophoresis (removing ions from the body), and not forpurposes of delivering medicament ions to the body.

The component 12 and the component 14 may generally consist of anyabsorbent material, or mixture of absorbent materials, that is capableof absorbing and holding the electrolytic solution, including solutionsthat include medicament ions and solutions that do not includemedicament ions. The particular absorbent material(s) used to form thecomponent 12 may generally be the same as, or different from, theabsorbent material(s) that are used to form the component 14. However,the buffer component 14 will always be different from the medicamentdelivery component 12, since the absorbent material of the buffercomponent 14 will be coated with the buffer coating or will otherwiseincorporate pH buffering agent, whereas pH buffering agent will never becoated on or incorporated into the absorbent material of the component12.

The absorbent material(s) of the components 12, 14 should be capable ofbeing fully wetted by the electrolytic solution and should be capable ofholding the electrolytic solution as a confluent liquid phase that isuniformly distributed throughout the absorbent material(s). Theabsorbent material should also be capable of quickly absorbing theelectrolytic solution. Since the bulk of the medicament ion deliveryfrom the electrode 10 involves medicament ions that originate in thecomponent 12, the component 12 should be sized to contain at leastenough medicament ions, at the selected medicament ion concentration inthe electrolytic solution, for one session of patient treatment. In oneembodiment of the electrode 10, the component 12 is sized to containabout 5.5 ml of the electrolytic solution of medicament ions.

The electrolytic solution may be introduced into the electrode 10 by anyconventional technique, such as by injecting electrolytic solution intothe component 12 or the component 14 with a hypodermic needle. Since thecomponents 12 and 14 are in contact with each other and are each made ofabsorbent material that is capable of absorbing the electrolyticsolution, the electrolytic solution will be absorbed into both thecomponent 12 and the component 14, no matter which of the components 12,14 the electrolytic solution is injected into. The components 12, 14 mayhold electrolytic solution that either does or does not containmedicament ions both prior to and during delivery of medicament ionsinto the body.

The medicament delivery component 12 and the buffer component 14 mayeach be multi-layered. However, the medicament delivery component 12 ispreferably formed as a single, monolithic layer, and the buffercomponent 14 is preferably formed as a single, monolithic layer.Formation of the components 12, 14 as single monolithic layerssimplifies the structure and manufacture of the electrode 10 and thecomponents 12, 14, while maintaining performance benefits of theelectrode 10, such as enhanced buffering uniformity.

The layer or layers of the medicament delivery component 12 and thebuffer component 14 may generally be made of any absorbent material, ormixture of absorbent materials, that has suitable absorbentcharacteristics and is capable of supporting the electrolytic solutionas a confluent liquid phase, so long as the distinct interface 21 ismaintained between the component 12 and the component 14. When themedicament delivery component 12 is multi-layered, different absorbentmaterials may be used to form different layers of the component 12.Likewise, when the buffer component 14 is multi-layered, differentabsorbent materials may be used to form different layers of thecomponent 14. Additionally, the component 12 and the component 14 may beformed of different absorbent materials.

The absorbent material of the medicament delivery component 12 and thebuffer component 14 may generally be based on any synthetic or naturalresinous material, such as a gum, polyurethane, or polyvinyl alcohol;any natural or synthetic fibrous material, such as polyester, rayon,wool, cotton, or cellulose; any colloidal material, such as that used toform gels, or any mixture of these, so long as the distinct interface 21is maintained between the component 12 and the component 14. Theresinous material may generally be any resinous polymer or copolymer ora mixture of resinous polymers or copolymers. The absorbent materialthat is used to make the components 12, 14 may generally have any solidor semi-solid form, such as that of foam, woven fabric, or gel. Nomatter what physical form the absorbent material takes, each form of theabsorbent material should be capable of quickly absorbing theelectrolytic solution and maintaining the electrolytic solution as aconfluent liquid phase within the absorbent material.

As used herein, a solid or semi-solid "foam" is a colloid that includes(1) a solid or -semisolid continuous phase that forms a threedimensional network and, prior to incorporation of electrolyticsolution, (2) a dispersed gaseous phase throughout the three dimensionalnetwork of the continuous phase. The continuous phase of the foam may beformed using either synthetic polymeric substances, such aspolyurethane, or naturally occurring polymeric substances, such asnatural rubber. As used herein, a "gel" is defined as a lyophiliccolloid that has coagulated to form either a rigid or a jelly-likesolid. The colloid of the gel includes a continuous phase that forms athree dimensional network and a disperse phase that forms a loosely-heldnetwork of linked molecules throughout the three dimensional network ofthe continuous phase. Gelatin is one example of a gel. As used herein, a"gum" is defined as any of a variety of natural occurring substancesobtained from plants, or synthetic equivalents of these naturallyoccurring substances, that are insoluble in organic solvents and formgelatinous or sticky solid or semi-solid solutions with water. Colloidalpolysaccharide substances are examples of gums.

The absorbent material of the components 12, 14, preferably takes theform of open cell solid foam that supports enhanced movement of anymedicament ions included in the electrolytic solution. Open cell solidfoam is more easily incorporated into automated manufacturing processesfor making the electrode 10 than other materials. Additionally, theinterconnection of pores and pore size range and distribution of opencell solid foams support enhanced, movement of medicament ions includedin the electrolytic solution. The open cell solid foam is preferablyopen cell polyurethane foam.

The polyurethane foam used to form the medicament delivery component 12preferably has an average pore density ranging from about 5 to about 200pores per linear inch (ppi) of polyurethane foam surface and an averagepore diameter ranging from approximately 150 micrometers toapproximately 1,000 micrometers. Polyurethane foams with these poredensity and diameter characteristics are available as the RYNEL™ seriesof polyurethane foams, such as AMREL™ 6 polyurethane foam, that may beobtained from Rynel, Ltd., Inc. of Boothbay, Me. Polyvinyl alcohol foamwith these pore density and diameter characteristics is available asKANEBO® polyvinyl alcohol foam that may be obtained from Shima AmericanCorporation of Elmhurst, Ill.

The polyurethane foam used to form the buffer component 14 preferablyhas an average pore density of about 70 to about 80 pores per linearinch (ppi) of polyurethane foam surface and an average pore diameterranging from about 200 micrometers to about 240 micrometers.Polyurethane foam with these pore density and diameter characteristicsmay be obtained as PREMIUM polyurethane foam from Foamex of Eddystone,Pa. or as FILTERCREST® polyurethane foam from Crest Foam Industries ofMoonachie, N.J.

Though the absorbent material of the components 12, 14 preferably takesthe form of monolithic layers, the absorbent material may alternativelyconsist of loose material, such as resinous particles or granules. Whenthe absorbent material of the component 12 is loose material, themedicament delivery component 12 should include suitable containmentlayers (not shown) for containing the absorbent material within themedicament delivery component 12. When the absorbent material of thecomponent 14 is loose material, the buffer component 14 should includesuitable containment layers (not shown) for containing the absorbentmaterial within the buffer component 14.

The absorbent material(s) that are used to form the medicament deliverycomponent 12 and the buffer component 14 should be highly absorbent,should have a relatively large specific absorbency, and should absorbthe electrolytic solution at a relatively high rate. High absorbency isneeded so that the surface area and weight of the components 12, 14, andthe dimensions and weight of the electrode 10 can be minimized withoutsacrificing the quantity of any medicament ions that are delivered bythe electrode 10. The absorbent material(s) need to have a relativelyhigh rate of absorption so that the electrolytic solution may be quicklyplaced in the medicament delivery component 12 and the buffer component14. The relatively high rate of absorption also minimizes or eliminateslosses of electrolytic solution and any medicament ions from theelectrode 10 during incorporation of the electrolytic solution into thecomponents 12, 14.

The absorbent material(s) of the components 12, 14 should be capable ofabsorbing at least about 500 ml of electrolytic solution per squaremeter of absorbent surface within about 5 seconds or less. Preferably,the absorbent material(s) should be capable of absorbing at least about1,000 ml of electrolytic solution per square meter of absorbent materialsurface within about 5 seconds or less. More preferably, the absorbentmaterial should be capable of absorbing at least about 2,000 ml ofelectrolytic solution per square meter of absorbent material surfacewithin about 5 seconds or less. Still more preferably, the absorbentmaterial should be capable of absorbing at least about 3,500 to about4,000 ml of electrolytic solution per square meter of absorbent materialsurface within about 5 seconds or less.

For purposes of determining absorbency, the surface area of theabsorbent material is determined after the absorbent material has beenformed into the component 12 layer(s) and the component 14 layer(s).Each layer of the component 12 and each layer of component 14 will havemajor surfaces and minor surfaces. A thickness A of each layer of thecomponent 12 and a thickness B of each layer of the component 14 willtypically be orders of magnitude less than the length, the width, thediameter, or other major dimension of the component 12 or component 14layers. The minor surfaces of the layers are defined as those surfacesthat encompass the thickness A or B of the layers, and the majorsurfaces are defined as those surfaces that do not encompass thethickness A or B of the layers.

The absorbency of the absorbent material(s) may be determined byapplying the electrolytic solution to any major surface of any absorbentmaterial layer of the component 12 and to any major surface of anyabsorbent material layer of the component 14. The surface area of anylayer of absorbent material, for purposes of evaluating absorbency, isthe surface area of the major surface of the layer to which theelectrolytic solution is applied.

Though the component 12 may include multiple layers of the absorbentmaterial, each of the layers of the component 12 preferably hasessentially the same major surface dimensions so that each layer isessentially coextensive with the other layers of the component 12.Though the layers of the component 12 do not necessarily need to havethe same thickness, the layers of the component 12 preferably do havesubstantially the same thickness to reduce manufacturing complexity.Similarly, though the component 14 may include multiple layers of theabsorbent material, each of the layers of the component 14 preferablyhas essentially the same major surface dimensions so that each layer isessentially coextensive with the other layers of the component 14.Though the layers of the component 14 do not necessarily need to havethe same thickness, the layers of the component 14 preferably do havesubstantially the same thickness to reduce manufacturing complexity.

The absorbent material(s) of the components 12, 14 should also have arelatively high specific absorbency of at least about 0.5 ml ofelectrolytic solution per gram of absorbent material. Preferably, thespecific absorbency of the absorbent material(s) should be at leastabout 1.0 ml of electrolytic solution per gram of absorbent material.More preferably, the specific absorbency of the absorbent material(s)should be at least about 3.0 ml of electrolytic solution per gram ofabsorbent material. Still more preferably, the specific absorbency ofthe absorbent material(s) should be at least about 5.0 ml ofelectrolytic solution per gram of absorbent material.

The absorbent material preferably is capable of quickly absorbing theelectrolytic solution at a rate of about 3 ml of electrolytic solutionper gram of absorbent material in less than about 3 minutes. Morepreferably, about 3 ml of electrolytic solution should be absorbed into1 g of absorbent material in less than about 1 minute. Still morepreferably, about 3 ml of electrolytic solution should be absorbed into1 g of the absorbent material in less than about 10 seconds. Thisability to quickly absorb the electrolytic solution is necessary tominimize, and preferably prevent, loss of electrolytic solution duringcharging of the components 12, 14 with the electrolytic solution and tominimize the time needed to charge the components 12, 14 with theelectrolytic solution.

Examples of resinous materials that may be used to prepare the absorbentmaterial of the components 12, 14 comprise various polymers andcopolymers, such as those that are capable of being formed as solid orsemi-solid foams, including polyurethanes; polyvinylpyrrolidones;polyvinyl alcohols; polyethylene oxides, such as POLYOX® polymers thatare manufactured by Union Carbide Corporation; polyacrylic acids, suchas CARBOPOL® polymers that are manufactured by B.F. Goodrich of Akron,Ohio; polyethylene glycols; polyacrylamides; cellulose derivatives, suchas hydroxyethyl cellulose, hydroxypropylmethylcellulose, low-substitutedhydroxypropylcellulose,and cross-linked Na-carboxymethylcellulose, suchas AC-DI-SOL™ polymers that are available from FMC Corporation ofPhiladelphia, Pa.; polyurethane-polyvinylpyrrolidone copolymers, such asHydromer® copolymers that are available from Hydromer Corp. ofSummerville, N.J.; and the like, along with blends thereof.

Some resinous materials, absent modification, do not have the absorbentcharacteristics specified above or the ability to maintain theelectrolyte solution as a confluent liquid phase. Therefore, theseresinous materials that lack the needed absorbent characteristics orconfluent liquid phase maintenance ability must be treated with anabsorption aid, such as a hydrophilic agent or a surfactant, to have theneeded absorbent characteristics and the ability to maintain theelectrolyte solution as a confluent liquid phase. For purposes of thisdisclosure, the absorption aid is defined as a chemical substance orsolution that facilitates movement of the electrolytic solution and anyincluded buffer suspension within voids of the absorbent material, suchas within pores of foam that serves as the absorbent material. Forpurposes of this disclosure, the hydrophilic agent is defined as achemical substance or solution that is capable of bonding with watermolecules of the electrolytic solution to facilitate movement of theelectrolytic solution and any included buffer suspension within thevoids of the absorbent material by hydrophilizing the void structure ofthe absorbent material. For purposes of this disclosure, the surfactantis defined as a surface active chemical substance or solution thatfacilitates movement of the electrolytic solution and any includedbuffer suspension within voids of the absorbent material by reducing thesurface tension of internal surfaces that define the voids within theabsorbent material.

The absorption aid is preferably non-ionic so that the absorption aiddoes not interfere with medicament ion delivery. Some examples ofmaterials that may serve as the hydrophilic agent include glycerine;organic or aqueous solutions of polyethylene glycol, polyethylene oxide,polyvinyl alcohol, peptide-based gelatins, such as carrageenan, andplant-based gums, such as karaya gum; as well as, mixtures of these. Forexample, the hydrophilic agent may be any of the solutions listed inTable 1:

                  TABLE 1    ______________________________________                        Hydrophilic Agent                        (Grams of Substance To    Substance           Grams of Water)    ______________________________________    Karaya Gum (dry powder)                        1:about 25 to about 35    Polyvinyl Alcohol   1:about 2.5 to about 3.5    (MW ranges from about 30,000 to    about 70,000 Daltons)    Polyethylene Glycol about 4 to about 6:1    (MW is about 3,350 Daltons)    Polyethylene Oxide  1:about 3 to about 5    (MW is about 1,000,000 Daltons)    Carrageenan (natural gelatin)                        1:about 35 to about 45    ______________________________________

Some examples of materials that may serve as the surfactant includeprimary alcohol ethoxylates, such as NEODOL 91-6 that is available fromShell Chemical Co.; secondary alcohol ethoxylates, such as TERGITOL15-S-17 that is available from Union Carbide Corp; DABCO® seriessurfactants, such as DABCO® DC193 and DABCO® DC5043 surfactants that areavailable from Air Products and Chemicals, Inc. of Allentown, Pa.;polyoxypropylene-polyoxyethylene block copolymer-type surfactants, suchas the PLURONIC® L62 and F88 PRILL surfactants that are available fromBASF Corporation of Mt. Olive, N.J., as well as, mixtures of these,organic or aqueous solutions of these, and mixtures of these and anyhydrophilic agent.

As those skilled in the art will readily recognize, particularabsorption aids may need to be added at different times to modifydifferent resinous materials. For example, many surfactants should beadded during preparation of resinous polymers to accomplish beneficialcross-linking between the surfactant and the polymer and incorporate thesurfactant into the polymer structure. As another example, somesurfactants are best added to some resinous materials after the resinousmaterial is formed, but before or during transformation of the resinousmaterial into foam. For still other resinous materials, some absorptionaids are best added after the resinous material has been formed intofoam. Glycerine; organic or aqueous solutions of polyethylene glycol,polyethylene oxide, polyvinyl alcohol, peptide-based gelatins, such ascarrageenan, and plant-based gums, such as karaya gum; and mixtures ofthese are examples of absorption aids that may be added after open cellpolyurethane foam is formed. Furthermore, for some resinous materials,some absorption aids may be optionally incorporated into the resinousmaterial at any time before, during, or after formation of the foam fromthe resinous material.

Some examples of resinous materials that may require treatment with theabsorption aid to be used as the absorbent material of the components12, 14 include various polymers and copolymers, including those that arecapable of being formed as solid or semi-solid foams, such aspolyethylene; polypropylene; polyisoprenes; polyalkenes; natural andsynthetic rubbers; polyvinylacetate copolymers; ethylene vinyl acetatecopolymers; polyamides, such as nylons; polyurethanes;polyvinylchloride; acrylic or methacrylic resins, such as polymers ofesters of acrylic or methacrylic acids with alcohols, such as n-butanol,n-pentanol, isopentanol, 2-methyl butanol, 1-methyl butanol, 1-methylpentanol, 2-methyl pentanol, 3-methyl pentanol, 2-ethyl butanol,isooctanol, n-decanol, or n-dodecanol, either alone or copolymerizedwith ethylenically unsaturated monomers, such as acrylic acid,methacrylic acid, acrylamide, methacrylamide, N-alkoxymethylacrylamides,N-alkoxymethylmethacrylamides, N-tert-butylacrylamide, and itaconicacid; N-branched alkyl maleamic acid, wherein the alkyl group has 10-24carbon atoms; glycol diacrylates; and blends thereof. Of course, theneed to treat a certain material with absorption aid will often dependon the characteristics of the particular form of the material, such asthe average pore density (pores per linear inch of material surface) offoams and the average pore diameter of the foams. Furthermore, the needto treat a particular material with absorption aid would be moot if themanufacturer or supplier of the material already incorporated absorptionaid into the material prior to delivery of the material.

Examples of fibrous materials that may be used as the absorbent materialof the components 12, 14 include woven fabrics, such as fleece or feltmade of polyester, rayon, cotton, wool. Examples of gums that may beused as the absorbent material of the components 12, 14 include naturalgums, such as chitosan, guar gum, and locust bean gum. Examples of gelsusable as the absorbent material include those based on variouspolysaccharides, such as pectin and starch, and those based onpolyhydroxyethylmethacrylate. Again, some of these fibrous materials,gums, and gels may require treatment with absorption aid to be used asthe absorbent material of the components 12, 14.

Though the buffer component 14 may be formed of woven fabric, gum, orgel, the buffer component 14 is preferably formed of an open cell foam,such as open cell polyurethane foam or open cell polyvinyl alcohol foam.Polyurethane and polyvinyl alcohol foams are preferred over wovenmaterial because the structure and pore arrangement of polyurethane foamand polyvinyl alcohol foams typically permit more uniform dispersal ofthe pH buffering agent, than does the structure and void arrangement ofwoven materials. Less uniform dispersal of the pH buffering agent in theabsorbent material may allow localized pH effects, such as areas of pHabove 8 or below 4, to form within the electrode 10. Polyurethane foamand polyvinyl alcohol foam are preferred over gums and gels becausepolyurethane and polyvinyl alcohol foams are typically capable ofabsorbing a much larger amount of electrolytic fluid in a much shorterperiod of time than gums and gels. Additionally, polyurethane foam andpolyvinyl alcohol foam typically more readily maintain the distinctinterface 21 as compared to gums and gels.

One type of open cell polyurethane foam that is used to form thecomponent 12 and/or the component 14 may be based upon one or morefoamable polyurethane prepolymers that are derived from toluenediisocyanate and that are marketed as part of the Hypol® group ofproducts by W.R Grace & Company of Woburn, Mass. Some examples ofsuitable Hypol® polyurethane prepolymers include Hypol® FHP 2000, Hypol®FHP 2002, and Hypol® FHP 3000 prepolymers. Open cell polyurethane foamthat is based upon Hypol® polyurethane prepolymer(s) typically exhibitsthe high absorbency and the relatively large specific absorbency thatthe absorbent material needs to have. Surfactant should typically beincorporated during the polymerization of the Hypol® polyurethaneprepolymer(s) to insure that the resulting absorbent material absorbsthe electrolytic solution at a relatively high rate.

The buffer component 14 that is formed of absorbent material takes theform of a support matrix that accepts, holds, and immobilizes the pHbuffering agent. The support matrix of the buffer component 14 alsoaccepts and holds a sufficient amount of electrolytic solution tosupport current flow between the conductive terminal 18 and the skin orbetween the skin and the conductive terminal 18. The pH buffering agentmay be coated onto a surface of the buffer component 14 as the buffercoating (not shown) that faces, and is in contact with, the conductivecomponent 16. Preferably, however, the pH buffering agent isheterogeneously dispersed throughout the buffer component 14, ratherthan being applied to the buffer component 14 as the buffer coating.

The pH buffering agent of the buffer component 14 neutralizes hydrogenions or hydroxide ions that are generated by electrolysis of water whencurrent is applied to the iontophoresis system that includes theelectrode 10. Hydrogen ions and hydroxide ions are examples of adverseions that are not intended for delivery into the body. If the anode ofthe iontophoresis system is structured like the electrode 10, the pHbuffering agent may include basic elements that neutralize hydrogen ionsgenerated at the anode. If the cathode of the iontophoresis system isstructured like the electrode 10, the pH buffering agent may includeacidic elements that neutralize hydroxide ions generated at the cathode.

One significant benefit of heterogeneously dispersing the pH bufferingagent throughout the buffer component 14 is the ability to closely andaccurately control the dosage of the pH buffering agent that is includedin the electrode 10. For example, the method of the present inventionpermits a predetermined amount of pH buffering agent to be measured andfully incorporated into the absorbent material of the buffer component14.

The technique for attaching the pH buffering agent as the buffer coatingon the buffer component 14 entails applying an aqueous or organicsuspension or slurry of the pH buffering agent onto a surface of theabsorbent material. The buffer component 14 is then placed in a warmoven to remove moisture from the buffer coating of pH buffering agent oris allowed to air dry. Techniques such as these are labor intensive andare difficult to control. These techniques do not permit close controlof the quantity of pH buffering agent that is associated with the buffercomponent 14.

For example, variables controlling how much buffering agent actuallysticks to the absorbent material, such as the adhesive characteristicsof the buffer coating, may change with time. Also, pH buffering agentthat adheres less strongly to the absorbent material may be easilyabraded or otherwise separated from the buffer component 14, especiallyduring electrode component manufacture and assembly. Thus, to makeelectrodes that adequately maintain a safe pH range proximate the skin,it is typically necessary to apply as much as five times more pHbuffering agent to form the buffer coating of the buffer component 14than is chemically necessary for the actual neutralization of hydrogenions or hydroxide ions that are formed after about forty minutes ofiontophoresis.

One technique for heterogeneously dispersing the pH buffering agentwithin the buffer component 14 entails forming a buffer suspension bymixing the pH buffering agent with any carrier that is capable of beingquickly absorbed into the absorbent material. Then, the buffersuspension is applied to the absorbent material to disperse the pHbuffering agent within the absorbent material of the buffer component14. This technique works best when the absorbent material is a resinousmaterial that is in the form of a solid or semi-solid foam, though thetechnique may also be used when the absorbent material is fibrousmaterial, such as woven fabric. This technique is believed to beunsuitable when the absorbent material is a resinous material in theform of a gum or a gel because of structural characteristics of gums andgels that would tend to inhibit dispersal of the pH buffering agent inthe absorbent material using this carrier-based technique.

The buffer suspension of the pH buffering agent and the carrier isapplied to the buffer component 14 to permit absorption of the carrierinto the buffer component 14 and dispersal of the pH buffering agentwithin the component 14. The physical characteristics of the carrier,such as the viscosity and the surface tension of the carrier, should beadequate to permit the carrier to uniformly disperse the pH bufferingagent throughout the buffer component 14. For example, the surfacetension of the carrier preferably ranges from about 50 dyne/cm to about70 dyne/cm at 20° C. and the viscosity of the carrier preferably rangesfrom about 1,300 cP to about 1,700 cP at 20° C. Some examples ofmaterials that may suitably serve as the carrier include glycerine;organic or aqueous solutions of polyethylene glycol, polyethylene oxide,polyvinyl alcohol, peptide-based gelatins, such as carrageenan, andplant-based gums, such as karaya gum; and mixtures of these.

Alternatively, the carrier may consist of a mixture of water and one ormore dispersants that is capable of uniformly dispersing the pHbuffering agent in the water. Examples of suitable dispersants includepolycarboxylic acids, such as polymethacrylates, includingpolymethacrylates available as Tamol® dispersants, Acusol® dispersants,and Acumer® dispersants from Rohm and Haas Co. of Philadelphia, Pa. Someparticular examples of suitable Tamol® dispersants include Tamol® 850dispersant and Tamol® 960 dispersant, and some particular examples ofsuitable Acusol® dispersants include Acusol® 445 dispersant and Acusol®445N dispersant. When the dispersant is used, the dispersant and waterare mixed to form the carrier. The amount of dispersant that is mixedwith water is preferably selected so that the surface tension of thecarrier ranges from about 50 dyne/cm to about 70 dyne/cm at 20° C. andthe viscosity of the carrier preferably ranges from about 1,300 cp toabout 1,700 cP at 20° C. The pH buffering agent, such as ion exchangeresin, is subsequently mixed with the carrier to form the buffersuspension. The buffer suspension is then applied to the buffercomponent 14 to permit absorption of the carrier into the buffercomponent 14 and dispersal of the pH buffering agent within thecomponent 14.

The pH buffering agent that is blended with the carrier may be in theform of granules or particles, such as ion exchange resin particles. Theparticle size of the pH buffering agent should be sufficiently large toimmobilize or otherwise prevent any significant movement of the pHbuffering agent within the absorbent material. However, the size of theparticles should also be small enough to permit most of the particles toremain in suspension in the carrier for at least about an hour, withoutany agitation or stirring of the buffer suspension. The pH bufferingagent particles should also be sufficiently small to prevent theabsorbent material of the buffer component from filtering out more thana de minimis amount of buffering agent particles, or otherwiseinterfering with substantially uniform dispersal of buffering agentparticles within the buffer component 14.

For example, when the material of the buffer component 14 has pore sizesranging from about 200 micrometers to about 240 micrometers, the size ofthe buffering agent particles should be less than 240 micrometers andshould preferably be less than about 200 micrometers, such as within arange from about 25 micrometers to about 150 micrometers. If theparticles are large enough to interfere with substantially uniformdispersal of the particles within the buffering component 14, theparticles should be ground to a size that will not interfere withsubstantially uniform dispersal of the particles within the bufferingcomponent 14.

There are several additional techniques for heterogeneouslyincorporating the pH buffering agent in the absorbent material of thebuffer component 14. Each of these techniques causes the pH bufferingagent to become physically entrapped within the absorbent material. Whenusing these techniques, the molecular weight and particle size of any pHbuffering agent that is used should be sufficiently large to immobilizeor otherwise prevent any significant movement of the pH buffering agentwithin the absorbent material. Preferably, the molecular weight of thepH buffering agent ranges from about 5,000 to about 10,000 daltons toeffectively immobilize the buffer in the buffer component 14.

As one alternative, the buffer component 14 may be formed byheterogeneously incorporating the pH buffering agent in one or moreprecursors of the absorbent material, prior to reacting the precursors.This technique works particularly well when the absorbent material isbased on resinous material, such as resinous polymer or copolymer or amixture of resinous polymer and/or copolymer. For example, the pHbuffering agent may be mixed with one or more prepolymer components ofresinous material, prior to polymerizing the prepolymer components toform the resinous material.

As another alternative for heterogeneously dispersing pH buffering agentin the absorbent material, the buffer component 14 may be formed as ahydrogel by casting a suitable mixture of the pH buffering agent,powdered gel particles, and water to form gel layer(s). The gel that isused in forming the buffer component 14 in this manner may be based onvarious polysaccharides, such as pectin and starch, and may be based onpolyhydroxyethylmethacrylate.

In yet another alternative, the buffer component 14 may be formed byheterogeneously mixing the pH buffering agent in the absorbent material,prior to forming the absorbent material into the layer(s) of the buffercomponent 14. This technique may be used to form a composite mixture ofthe absorbent material and the pH buffering agent. For example, thebuffer component 14 may be formed by mixing a gum with the pH bufferingagent to uniformly disperse the pH buffering agent in the gum.Alternatively, the pH buffering agent, powdered gum particles, and watermay be mixed to form the mixture of gum and pH buffering agent. Themixture of gum and pH buffering agent is then shaped, such as bycasting, to form gum layer(s). The gum that is used in forming thebuffer component 14 in this manner may be based on colloidalpolysaccharide substances, such as natural gums, including chitosan,guar gum, and locust bean gum.

In another alternative, the buffer component 14 may be formed byheterogeneously incorporating the pH buffering agent in resinousmaterial, such as resinous polymer or copolymer, prior to transformingthe resinous material into the absorbent material. For example, the pHbuffering agent may be melt blended with the resinous material afterpolymerization of prepolymer components of the resinous material andbefore the resinous material is transformed into the absorbent material,such as solid or semi-solid foam. When the absorbent material is in theform of foam, the absorbent product of this process is heterogenous pHbuffering foam. When the absorbent material is heterogeneous pHbuffering foam, the molecular weight of the pH buffering agent should beat least about 5000 daltons to help immobilize the pH buffering agent inthe heterogenous pH buffering foam.

Heterogenous pH buffering foam includes at least two distinct phases.For any electrode 10 that includes the heterogeneous pH buffering foam,each of the phases should be insoluble in the solvent portion of anyelectrolytic solution included in the electrode to help immobilizephysical movement of any component of the heterogeneous pH bufferingfoam within the electrode. The phases may each be solid or semi-solid innature. Alternatively, some phase(s) may be solid in nature, and otherphase(s) may be semi-solid in nature. One or more pH buffering agentsmake up one or more of the phases, and polymer foam or copolymer foammakes up the other phase(s).

The buffer component 14 may incorporate any pH buffering agent in anyform. For example, the pH buffering agent may be any ion-exchangematerial, such as ion-exchange resin that is organic in chemicalstructure. Additionally, the pH buffering agent may be anionic orcationic ion-exchange material. Furthermore, the buffer component 14 mayincorporate both anionic and cationic ion-exchange materials oramphoteric ion-exchange material. This permits interchangeable use ofthe electrode 10 as the anode, or the cathode of the iontophoresissystem or, alternatively, as the anode and the cathode of theiontophoresis system.

The pH buffering agent, such as the ion-exchange material, should becapable of maintaining the pH of the electrolytic solution within theelectrode 10 in a range of from about 4 to about 8 standard pH units toavoid irritating or burning the biological surface, such as the skin ofthe body. For example, the pH buffering agent should be capable ofholding about 0.1 milliequivalents of acid or about 0.1 milliequivalentsof base during an iontophoresis period of about 40 minutes or more whilemaintaining the about 4 to about 8 pH range of the electrolyticsolution. Preferably, the pH buffering agent is capable of holding about0.1 milliequivalents of acid and about 0.1 milliequivalents of baseduring an iontophoresis period of about 40 minutes or more whilemaintaining the about 4 to about 8 pH range of the electrolyticsolution.

The pH buffering agent should also have a relatively high bufferingcapacity to aid in minimizing the size and weight of the buffercomponent 14 while maintaining the about 4 to about 8 pH range of theelectrolytic solution during iontophoresis periods on the order of about40 minutes or more. At a minimum, the buffering capacity of the pHbuffering agent should be at least about 0.5 milliequivalents of acid orbase per gram of pH buffering agent. Preferably, the buffering capacityof the pH buffering agent should be at least about 1.0 milliequivalentsof acid or base per gram of pH buffering agent. More preferably, thebuffering capacity of the pH buffering agent should be at least about1.5 milliequivalents of acid or base per gram of pH buffering agent.Still more preferably, the buffering capacity of the pH buffering agentshould be at least about 1.5 milliequivalents of acid per gram of pHbuffering agent and at least about 1.5 milliequivalents of base per gramof pH buffering agent.

Examples of ion-exchange resins that arc suitable for use as the pHbuffering agent include various anion and cation exchange resins, ineither gel or macroreticular form, such as the Amberlite® series ofresins and the Duolite® series of resins available from Rohm & HaasCorporation and the Dowex® series of resins available from DowCorporation of Midland, Mich. Examples of suitable Amberlite® resinsinclude Amberlite® IRP-64, Amberlite® IRP-68, Amberlite® IRP-88,Amberlite® CG-50 and Amberlyst® A21 resins. Examples of suitableDuolite® resins include Duolite® C-433, Duolite® A-368, and Duolite®A-392S resins. Examples of suitable Dowex® resins include Dowex® WGR,Dowex® WGR-Z, and Dowex® MWA-1 resins. To aid in attaining the about 4to about 8 pH range in the electrode 10, the ion-exchange resin shouldpreferably be either weakly basic or acidic, be of fine particle size,and be pharmaceutical-grade gel-type resin.

One version of the ion exchange resin may be an ion-exchange copolymerthat is formed by reacting a first prepolymer and a second prepolymer.The first and second prepolymers may be polymerized to form theion-exchange copolymer using any suitable conventional copolymerizationtechnique. The first prepolymer may consist of a single monomericprecursor or may consist of a mixture of different monomeric precursors.Examples of monomeric precursors suitable for use as the firstprepolymer include alkanes, alkenes, and substituted benzenes, such asdivinyl benzene.

The second prepolymer may generally be any single monomeric ion-exchangeprecursor or a mixture of different monomeric ion-exchange precursors.Monomeric ion-exchange precursors may be formed by attaching one or moreion-exchange functional groups to any monomeric precursors using anyconventional chemical bonding technique, such as substitution orgrafting. At least one of the monomeric precursors that acts as thefirst prepolymer and at least one of the monomeric precursors that isused in forming the monomeric ion-exchange precursor should be differentfrom each other.

Examples of monomeric precursors suitable for use in making themonomeric ion-exchange precursor include substituted benzenes, such asdivinyl benzene. Other examples of monomeric precursors suitable for usein making the monomeric ion-exchange precursor include a variety ofurethanes, which may include a variety of different functional groups,such as (1) diol groups and diisocyanate groups and (2) triol groups andtri-isocyanate groups. Examples of ion-exchange functional groups thatare suitable for attachment to the monomeric precursor(s) includecarboxyl groups, amino groups, --SO₃ H groups, --OPO₃ H₂ groups. Thus,some examples of the monomeric ion-exchange precursor, i.e. the secondprepolymer, are acrylic acid and methacrylic acid.

One suitable ion-exchange copolymer is prepared by copolymerizingdivinyl benzene, which serves as the first prepolymer, and methacrylicacid, which serves as the second prepolymer. One suitable copolymer ofmethacrylic acid and divinyl benzene is represented by structuralformula I below: ##STR1##

One example of the methacrylic acid/divinyl benzene copolymer with thestructure of formula I is Amberlite® IRP-64, which is available fromRohm & Haas Co. of Philadelphia, Pa. Amberlite® IRP-64 has an x/y ratioof 12. Thus, an average monomer unit of the Amberlite® IRP-64 copolymerhas 24 methacrylic acid groups per divinyl benzene group. Additionally,the Amberlite® IRP-64 copolymer is about 4.5% by weight divinyl benzeneand about 95.5% by weight methacrylic acid. The Amberlite® IRP-64copolymer may be dispersed in the absorbent material of the buffercomponent 14, or applied as part of the buffer coating of the buffercomponent 14, when the cathode of the iontophoresis system has thestructure of the electrode 10.

When the anode of the iontophoresis system has the structure of theelectrode 10, a metal salt of the ion-exchange copolymer may bedispersed in the buffer component 14 or may be applied as part of thebuffer coating of the buffer component 14. The ion-exchange copolymermay be treated with a mineral acid, such as potassium chloride, toobtain the metal salt of the ion-exchange copolymer. Treatment of thecopolymer of graphic formula I with potassium chloride yields thecompound represented by graphic formula II, which is one example of asuitable metal salt of the ion-exchange copolymer: ##STR2##

One example of the copolymer metal salt with the structure of formula IIis Amberlite® IRP-88, which is available from Rohm & Haas Co. Amberlite®IRP-88 has an x/y ratio of 12. Thus, an average monomer unit of theAmberlite® IRP-88 copolymer has 24 metal salt groups of methacrylic acidper divinyl benzene group. The Amberlite® IRP-88 copolymer may bedispersed in the support matrix of the buffer component 14, or appliedas part of the buffer coating of the buffer component 14, when the anodeof the iontophoresis system has the structure of the electrode 10.

Continuing with FIG. 1, the conductive component 16 of the electrode 10conducts current that is applied to the terminal 18 and distributes thecurrent across an upper surface 22 of the buffer component 14. The uppersurface 22 faces the conductive component 16. The conductive component16 should uniformly distribute current across the upper surface 22.Preferably, the current density proximate the interface of the electrode10 and the skin does not exceed about 0.5 milliamperes per squarecentimeter of skin surface. Current densities proximate the skin ofhigher than about 0.5 milliamperes per square centimeter of skin surfaceincrease the likelihood of patient discomfort and irritation of theskin.

The conductive component 16 may be formed of any suitable conductivematerial. Preferably, the conductive component 16 is highly conductiveand has a maximum resistivity of about 10 ohms-cm to enhance theefficiency of the electrode 10. The conductive component 16 should alsobe flexible so the electrode 10 can closely conform to the shape of theskin. The conductive component 16 should be impermeable to fluids, suchas electrolytic solution contained in the electrode 10, to preventdegradation of the electro-chemical characteristics of the electrode 10.Examples of suitable materials for the conductive component 16 include athin sheet or film of carbon, carbon-loaded silicon rubber, metal foil,electronically-conductive cloth, and electronically-conductive adhesive.

The adhesive covering 20 is an adhesive tape that serves as a structuralsupport component that helps to hold the components 12, 14, 16 togetherand is also useful for securing the electrode 10 to the skin (notshown). The adhesive covering 20 additionally prevents seepage ofelectrolytic solution along the skin away from the electrode 10. Theadhesive covering 20 is affixed to an upper surface 24 of the conductivecomponent 16 and is preferably also affixed to an upper surface 26 ofthe medicament delivery component 12. The upper surfaces 24, 26 eachface away from the skin and toward the adhesive covering 20. Themedicament delivery component 12 is preferably somewhat wider than thecomponents 14, 16 to permit adhesive contact between the covering 20 andthe upper surface 26.

The adhesive covering 20 should be highly flexible so that the adhesivecovering 20 readily conforms to the skin. The adhesive covering 20 maybe formed on any suitable material, such as a thin layer of polyvinylchloride foam or polyethylene foam that is coated with medical-gradepressure-sensitive adhesive. It is to be understood that other suitableflexible materials that are coated with adhesive may be used to form theadhesive covering 20.

The electrode 10 may also include a release layer 28 that is locatedadjacent to, and in contact with, the medicament delivery component 12.Portions of the adhesive covering 20 that are not in contact with thecomponents 12, 14, and 16 are releasably attached to the release layer28 to prevent the electrode 10 from becoming undesireably stuck to otherobjects prior to use. At the time of use, the release layer 28 is peeledfrom the electrode 10 to permit placement of the component 12 adjacentto the skin and to permit adhesive attachment of the adhesive covering20 to the skin.

Though not depicted, the electrode 10 may alternatively include awicking layer (not shown) between the component 12 and the release layer28. When the wicking layer is included, the component 12 is preferablycoextensive with the components 14 and 16. The wicking layer is foldedat the peripheral edge of the component 12 to conform to the peripheraledge of at least the component 12 and is fixedly attached to theadhesive surface of the adhesive covering 20. With this arrangement, thewicking layer and the adhesive covering 20 cooperate to hold thecomponents 12, 14, 16 together within the electrode 10. When theelectrode 10 is placed against the skin, after removal of the releaselayer 28, the wicking layer is in contact with the skin and separatesthe component 12 from the skin. It has been found that the wicking layernegligibly, if at all, affects the medicament ion deliverycharacteristics of the electrode 10.

Examples of suitable materials for the wicking layer include non-wovenblends of polyester and cellulose, such as Durx® 670 or Durx® 770, whichare available from Berkshire Corporation of Great Barrington, Mass.Other examples of suitable materials for the wicking layer includeblends of cellulose and polyethylene terephthalate, such as Unilayer®1+2 or Unispun® 200, which are available from Midwest Filtration Companyof Fairfield, Ohio. Still further examples of suitable materials for thewicking layer include various non-woven and interlining fabricsavailable from Hollingsworth & Vose Company of Floyd, Va.

Throughout the drawings, like elements are referred to using likereference characters.

The electrode 10 may be modified to form an electrode 110, as in FIG. 2,by omitting the conductive component 16. The electrode 110 also has abuffer component 114 that is substituted in place of the buffercomponent 14. The buffer component 114 has the same compositional andstructural features as the buffer component 14, with one exception.Specifically, conductive filler (not shown) is incorporated andimmobilized in the buffer component 114 to make the buffer component 114conductive. All aspects of the buffer component 114, other thanincorporation of the conductive filler, are the same as those of thebuffer component 14. For example, the absorbent materials that is usedto form the buffer component 114 are the same as the absorbent materialsprescribed for use in forming the buffer component 14. As anotherexample, the absorbent material of the buffer component 114 should havethe same absorbent characteristics as the buffer component 14.

In the electrode 110, the conductive terminal 18 is attached to thebuffer component 114 to direct current flow into the buffer component114. The buffer component 114 and the medicament delivery component 12each conduct current that is applied to the terminal 18. The currentflowing through the medicament delivery component 12 and the buffercomponent 114 provides motive force that drives medicament ions into thebody. Also, in the electrode 110, the adhesive covering 20 is affixed tothe buffer component 114, the medicament delivery component 12, and therelease layer 28, rather than to the conductive component 16, themedicament delivery component 12, and the release layer 28, as in theelectrode 10.

The conductive filler may be any conductive form of carbon black;powdered graphite; carbon fibers; a metal powder, such as zinc powder,silver powder, and silver/silver chloride powder; or any other knownelectronically conductive filler material. The conductive filler may bedispersed throughout the buffer component 114, such as by uniformlymixing the conductive filler in the structural matrix of the buffercomponent 114 using any known mechanical means. Additionally, theparticles of the conductive filler should have a shape and size that isadequate to immobilize the conductive filler within the buffer component114.

Alternatively, the conductive filler may be incorporated in the buffercomponent 114 of the electrode 110 to create an electric potentialbetween the upper surface 116 and a lower surface 118 of the buffercomponent 114. The upper surface 116 faces toward the adhesive covering20, and the lower surface 118 faces away from the adhesive covering 20.The particles of conductive filler should have a shape and size that isadequate to immobilize the conductive filler within the buffer component114. If the anode of the iontophoresis system is structured like theelectrode 110, the electric potential should decrease between thesurface 116 and the surface 118. If the cathode of the iontophoresissystem is structured like the electrode 110, the electric potentialshould increase between the surface 116 and the surface 118.

In this alternative form, the conductive filler may be distributed on agraduated basis within the buffer component 114 or may be concentratedproximate the upper surface 116, as appropriate, to generate the changein potential needed for the anode and the cathode to function in theiontophoresis system. However, the conductive filler should not beconcentrated proximate the lower surface 118 of the buffer component114, since such concentration proximate the lower surface 118 wouldinhibit the ability of the pH buffering agent to neutralize waterelectrolysis products prior to diffusion of water electrolysis productsacross the lower surface 118 and into the medicament delivery component12.

Current entering the buffer component 114 should be uniformlydistributed across the upper surface 116 of the buffer component 114.Preferably, the current density proximate the interface of themedicament delivery component 12 and the skin does not exceed about 0.5milliamperes per square centimeter of skin surface. Current densitiesproximate the skin surface of higher than about 0.5 milliamperes persquare centimeter of skin surface increase the likelihood of patientdiscomfort and irritation of the skin.

Though not depicted, the electrode 110 may alternatively include thewicking layer (not shown) that was previously described with referenceto the electrode 10. In the electrode 110, the wicking layer separatesthe component 12 and the release layer 28. In the electrode 110 thatincludes the wicking layer, the component 12 is preferably coextensivewith the component 114. The wicking layer is folded at the peripheraledge of the component 12 to conform to the peripheral edge of at leastthe component 12 and is fixedly attached to the adhesive surface of theadhesive covering 20. With this arrangement, the wicking layer and theadhesive covering 20 cooperate to hold the components 12, 114, togetherwithin the electrode 110.

The electrode 10 may be modified to form an electrode 210, as in FIG. 3,by making a few minor adjustments. The electrode 210 includes themedicament delivery component 12 and the buffer component 14. The buffercomponent 14 is located adjacent to and in direct contact with themedicament delivery component 12. pH buffering agent is preferablydispersed uniformly throughout the buffer component 14. However, thebuffer coating (not shown) that includes the pH buffering agent, asdiscussed in connection with the electrode 10, may alternatively beapplied to an outer surface of the component 14. The electrode 210further includes the conductive component 16 that is located adjacent toand in contact with the buffer component 14. In the electrode 210, thebuffer component 14 is thus located between and in contact with themedicament delivery component 12 and the conductive component 16.

Though the component 12 and the component 14 are located adjacent toeach other and are in direct contact with each other, the distinctinterface 21 or boundary between the absorbent material of the component12 and the absorbent material of the component 14 should exist in theelectrode 210. The interface 21 is preferably smooth in nature. Theabsorbent material of the component 12 and the absorbent material of thecomponent 14 should not merge with each other to any degree at theinterface 21 between the components 12, 14.

The electrode 210 additionally includes the conductive tab or terminal18, such as the conductive snap connector, that is attached inelectrical communication to the conductive component 16. The electrode210 also incorporates the adhesive covering 20 that is useful forsecuring the electrode 210 to the skin (not shown). The adhesivecovering 20 is affixed to the upper surface 24 of the conductivecomponent 16 in the electrode 210. The electrode 210 may also includethe release layer 28 to prevent the adhesive covering 20 from becomingundesireably attached to a surface, such as a packaging surface, duringstorage of the electrode 210 prior to placement of the electrode 210against the skin.

In the electrode 210, the components 12, 14, 16 are substantiallycoextensive with each other. Preferably, the components 12, 14 fullyoverlap each other and the components 14, 16 fully overlap each other.To avoid any need for adhesive activity between the components 12, 14,and between the components 14, 16, a wicking layer 212 is provided inthe electrode 210 to secure the components 12, 14, 16 together and withrespect to the adhesive covering 20. The wicking layer 212 rests againsta major surface 214 of the component 12 that faces away from thecomponent 14 and is secured to an adhesive surface 216 of the adhesivecovering 20. With this arrangement, the wicking layer 212 and theadhesive covering 20 cooperate to hold the components 12, 14, 16together within the electrode 210. The wicking layer 212 may be made ofany of the materials mentioned with respect to the wicking layer inconnection with the electrode 10. Despite the presence of the wickinglayer 212, it is to be understood that it is acceptable for thecomponents 12, 14 to adhere to each other and for the components 14, 16to adhere to each other.

The release layer 28 rests against the wicking layer 212 opposite thecomponent 12 and is affixed to exposed portions of the adhesive surface216 where the wicking layer 212 is not affixed and does not extend overthe adhesive surface 216. The release layer 28 is removed from theelectrode 210 when it is desired to place the electrode 210 against theskin. When the electrode 210 is placed against the skin, after removalof the release layer 28, the wicking layer is in contact with the skinand separates the component 12 from the skin. It has been found that thewicking layer 212 negligibly, if at all, affects the medicament iondelivery characteristics of the electrode 210.

Though not depicted in FIG. 3, it is also to be understood that thebuffer component 114 may be substituted in place of the buffer component14 and the conductive component 16 in the electrode 210. When the buffercomponent 114 is substituted in place of the buffer component 14 and theconductive component 16 in the electrode 210, the conductive tab orterminal 18, such as the conductive snap connector, is attached inelectrical communication to the buffer component 114 and the adhesivecovering 20 is affixed to an upper surface of the buffer component 114that faces away from the component 12.

All subsequent statements about the electrode 10 apply equally to theelectrodes 110 and 210, unless otherwise indicated. Also, all subsequentstatements about the buffer component 14 apply equally to the buffercomponent 114, unless otherwise indicated.

Though prior comments about the iontophoresis system mentioned deliveryof medicament ions from one or the other of the electrodes that isstructured like the electrode 10, both iontophoresis system electrodesmay be used to deliver medicament ions. When each electrode of theiontophoresis system delivers medicament ions to the body, those skilledin the art will recognize that each electrode of the iontophoresissystem acts as the active electrode for the respective medicament ionsdelivered from the respective electrode of the iontophoresis system.Similarly, each electrode of the iontophoresis system acts as the returnelectrode for the respective electrode of the iontophoresis system thatis delivering medicament ions to the body.

One necessary step in making the electrode 10 is to produce themedicament delivery component 12 that is made of the absorbent material.Examples of the absorbent material that may used to make the medicamentdelivery component 12 include any of the resinous materials listedabove, including resinous polymers and copolymers and mixtures ofresinous polymers and/or resinous copolymers that are in the form ofsolid or semi-solid foams, such as solid open-cell polyurethane foam orsemi-solid polyurethane-polyvinylpyrrolidone copolymer foam; wovenfabrics, such as polyester, cotton, rayon, and woolen fleece or matting;gums, including natural gums, such as chitosan, guar gum, and locustbean gum; and gels, including those based on various polysaccharides,such as pectin and starch, and those based onpolyhydroxyethylmethacrylate.

The absorbent material that is used to form the medicament deliverycomponent 12 layer(s) may be obtained using any conventional techniquefor preparing the absorbent material. As explained above, some absorbentmaterials that are used to form the component 12 layer(s) mustincorporate an absorption aid to have the absorbent characteristicsrequired by the component 12. For these absorbent materials, theabsorption aid may be incorporated into the absorbent material before,during, or after preparation of the absorbent material, as appropriatefor the particular absorbent material and the particular absorption aid.Absorption aid may be incorporated into the absorbent material prior toor during formation of the absorbent material using any conventionaltechnique that is appropriate for the particular absorption aid and theparticular absorbent material. Details about application of absorptionaid, in the form of the hydrophilic agent, to absorbent material afterformation of the absorbent material are provided below.

After the absorbent material is prepared, the absorbent material issubjected to a suitable shaping process, such as extrusion, injectionmolding, compression molding, injection compression molding, or transfermolding, as appropriate for the particular absorbent material, to formthe layer(s) of the medicament delivery component 12. The absorbentmaterial layer(s) of the component 12 are subsequently cured, asnecessary and appropriate for the particular absorbent material.

For absorbent materials that require absorption aid incorporation tohave the absorbance characteristics needed by the component 12,absorption aid, such as the hydrophilic agent, may sometimes beincorporated after the particular absorbent material is produced, asthose skilled in the art will recognize. The method of treatingabsorbent material of the medicament delivery component 12 with thehydrophilic agent involves several steps. First, the hydrophilic agentis applied to the absorbent material of the medicament deliverycomponent 12 until the absorbent material is saturated with thehydrophilic agent. Some suitable techniques for applying the hydrophilicagent to the absorbent material include spraying the absorbent materialwith the hydrophilic agent or soaking the absorbent material in thehydrophilic agent.

After saturating the absorbent material of the medicament deliverycomponent 12 with the hydrophilic agent, any excess of the hydrophilicagent is removed from the absorbent material by physical means. Examplesof the physical means used to remove excess amounts of hydrophilic agentfrom the absorbent material include squeezing, pressing, and wringing.The hydrophilic agent is preferably selected to prevent the hydrophilicagent from flowing or oozing out of the absorbent material after thephysical means remove any excess of the hydrophilic agent from theabsorbent material. Finally, the absorbent material that includes thehydrophilic agent is warmed in an oven at a temperature of approximately100° C. or less to remove moisture from the layer(s) of the medicamentdelivery component 12. The absorbent is dried in the oven until theweight of the component 12 remains steady.

Another necessary step in making the electrode 10 is to prepare thebuffer component 14. In preparing the buffer component 14, the pHbuffering agent may be heterogeneously dispersed within the absorbentmaterial of the buffer component 14. Alternatively, the pH bufferingagent may be applied as part of the buffer coating to the absorbentmaterial of the buffer component 14.

One suitable absorbent material for use in forming the buffer component14 is reticulated, fine pore, polyurethane foam with about 70 to about80 pores per linear inch (ppi) of absorbent material surface and anaverage pore diameter ranging from about 200 to about 240 micrometers. A2.5 mm thick disk that is made of this type of polyurethane foam weighsabout 0.09 grams when the disk has a diameter of about 4.1 cm and asurface area of about 13.2 cm².

As mentioned, the pH buffering agent of the buffer component 14 ispreferably capable of holding about 0.1 milliequivalents of acid andabout 0.1 milliequivalents of base during an iontophoresis period ofabout 40 minutes or more while maintaining the about 4 to about 8 pHrange of the electrolytic solution. Patients can generally toleratecurrent densities of less than about 0.5 mA/cm² during iontophoresisthat occurs for periods of about 40 minutes. At a current density of 4mA, the skin contact surface area of the electrode 10 therefore shouldbe greater than about 8 cm², such as about 10 cm², 13 cm², or 22 cm².

A 50/50 mixture, by weight, of Amberlite® IRP-64 copolymer andAmberlite® IRP-88 copolymer generally has about 1.67 meq of each acidand each base per gram of the Amberlite® copolymer mixture. Therefore,when the pH buffering agent is a 50/50 mixture, by weight, of theAmberlite® IRP-64 and IRP-88 copolymers, the buffer component 14 shouldcontain at least about 0.06 grams of the Amberlite® copolymer mixture tobe capable of holding about 0.1 milliequivalents of acid and about 0.1milliequivalents of base while maintaining the about 4 to about 8 pHrange of the electrolytic solution. Therefore, when the buffer component14 is made of a 2.5 mm thick disk of the reticulated polyurethane foamthat has a diameter of about 4.1 cm and a surface area of about 13.2cm², the ratio of the weight of the Amberlite® copolymer mixturerelative to the weight of reticulated polyurethane foam of the 4.1 cmdiameter disk may be as low as about 1.1 grams of the Amberlite®copolymer mixture per gram of the reticulated polyurethane foam.

The buffer component 14 may alternatively contain about 0.18 grams ofthe Amberlite® copolymer mixture to give the buffer component a safetyfactor of about 3 that permits the buffer component 14 to hold about 0.3milliequivalents of acid and about 0.3 milliequivalents of base whilemaintaining the about 4 to about 8 pH range of the electrolyticsolution. Preferably, the buffer component 14 contains about 0.3 gramsof the Amberlite® copolymer mixture to give the buffer component asafety factor of about 5 that permits the buffer component 14 to holdabout 0.5 milliequivalents of acid and about 0.5 milliequivalents ofbase while maintaining the about 4 to about 8 pH range of theelectrolytic solution. Therefore, when the buffer component 14 is madeof a 2.5 mm thick disk of the reticulated polyurethane foam that has adiameter of about 4.1 cm and a surface area of about 13.2 cm², the ratioof the weight of the Amberlite® copolymer mixture relative to the weightof the reticulated polyurethane foam of the 4.1 cm diameter disk ispreferably about 3.3 grams of the Amberlite® copolymer mixture per gramof reticulated polyurethane foam.

When the dimensions of the reticulated polyurethane foam disk of thecomponent 14 are changed, the weight of the foam disk will typicallychange. Those skilled in the art will therefore understand that theratio of the weight of the 50/50 mixture of Amberlite® IRP-64 and IRP-88copolymers to the weight of the reticulated polyurethane foam will needto be modified, when the dimensions of the reticulated polyurethane foamdisk of the component 14 are modified, in proportion to the change inweight of the foam disk, to permit the buffer component 14 to hold thedesired number of milliequivalents of acid and the desired number ofmilliequivalents of base while maintaining the about 4 to about 8 pHrange of the electrolytic solution.

When the pH buffering agent is applied to the absorbent material as thebuffer coating, the absorbent material is first prepared and formed intothe layer(s) of the buffer coating 14. Examples of the absorbentmaterial that may be coated with the buffer coating include any of theresinous materials listed above, including resinous polymers andcopolymers and mixtures of resinous polymers and/or resinous copolymersthat are in the form of solid or semi-solid foams; woven fabrics, suchas polyester, rayon, cotton, and woolen fleece or matting; gums,including natural gums, such as chitosan, guar gum, and locust bean gum;and gels, including those based on various polysaccharides, such aspectin and starch, and those based on polyhydroxyethylmethacrylate.

The absorbent material that is used to form the buffer component 14layer(s) may be obtained using any conventional technique for preparingthe absorbent material. As explained above, some absorbent materialsthat are used to form the component 14 layer(s) will need to incorporatean absorption aid to have the absorbent characteristics required by thecomponent 14. For these absorbent materials, the absorption aid may beincorporated into the absorbent material before, during, or afterpreparation of the absorbent material, as appropriate for the particularabsorption aid and the particular absorbent material. Absorption aid maybe incorporated into the absorbent material prior to or during formationof the absorbent material using any conventional technique that isappropriate for the particular absorption aid and the particularabsorbent material.

Details about application of absorption aid, such as absorption aid inthe form of the hydrophilic agent, to absorbent material after formationof the absorbent material are provided above in connection with thecomponent 12. When absorption aid is applied after preparation of theabsorbent material, the absorption aid application process and theprocess of forming the absorbent material into the buffer component 14should be completed before the buffer coating of pH buffering agent isapplied to the absorbent material. Otherwise, the absorption aidapplication and shaping process would be expected to cause removal of atleast some of the buffer coating from the buffer component 14.

If it is desired, the buffer component 114 may be substituted in placeof the buffer component 14 and the conductive component 16. The buffercomponent 114 has the same compositional and structural features as thebuffer component 14, except that conductive filler (not shown) isincorporated and immobilized in the buffer component 114 to make thebuffer component 114 conductive. The conductive filler is preferablyincorporated into the absorbent material prior to shaping of theabsorbent material into the layer(s) of the buffer component 114.

After the absorbent material is prepared, but prior to application ofthe buffer coating, the absorbent material is subjected to a suitableshaping process, such as extrusion, injection molding, compressionmolding, injection compression molding, or transfer molding, asappropriate for the particular absorbent material, to form the layer(s)of the buffer component 14. The absorbent material layer(s) of thecomponent 14 are subsequently cured, as necessary and appropriate forthe particular absorbent material.

After the absorbent material is formed into the layer(s) of the buffercomponent 14 and, if the buffer component 14 includes multiple layers ofthe absorbent material, the absorbent material layers are laminatedtogether. Then, if the buffer component 14 includes multiple layers ofthe absorbent material, the buffer coating is applied to one exposedmajor surface of one of the outermost layers of absorbent material.Alternatively, if the buffer component includes only one layer ofabsorbent material, the buffer coating is applied to one of the majorsurfaces of the absorbent material layer. After applying the buffercoating, the buffer component 14 is positioned between the medicamentdelivery component 12 and the conductive component 16, with the buffercoating facing and in contact with the conductive component 16. When thebuffer component takes the form of the buffer component 114, the buffercomponent 114 is positioned between the medicament delivery component 12and the adhesive covering 20, with the buffer coating facing and incontact with the adhesive covering 20.

Application of the buffer coating to the absorbent layer of the buffercomponent 14 involves several different steps. First, the pH bufferingagent, such as ion-exchange resin, is mixed with de-ionized water. Theratio of ion-exchange resin to water in the buffer coating, prior toapplication of the buffer coating to the absorbent material, should bein the range of about 150 to about 400 grams of ion exchange resin perliter of water and is preferably about 300 grams of ion-exchange resinper liter of water. Prior to application of the buffer coating to theabsorbent material, the buffer coating that incorporates ion exchangeresin should have the consistency of a slurry so that the coating may beapplied to the absorbent material of the component 14 using a flowtechnique, such as a waterfall-type technique.

After the pH buffering agent and the water are mixed, the absorbentmaterial of the component 14 may be placed on an open wire conveyor andpassed under a flowing stream of the aqueous slurry of pH bufferingagent so that the aqueous slurry accumulates as the buffer coating onone side of the absorbent material to the desired thickness. Where thedensity of ion exchange resin in the aqueous slurry is about 0.2 gramsof ion exchange resin per milliliter of slurry, the bulk density of theion exchange resin is about 0.6 grams per milliliter of ion exchangeresin, and the desired amount of ion-exchange resin to be applied to theabsorbent material as part of the buffer coating is about 0.35 grams ofion-exchange resin, the thickness of the buffer coating that is appliedto the surface of the absorbent material, as measured after the buffercoating is dried, will need to be about 0.4 mm to about 0.8 mm when thearea of the surface to be coated is about 10 cm², about 0.3 mm to about0.6 mm when the area of the surface to be coated is about 13 cm², andabout 0.2 mm to about 0.3 mm when the area of the surface to be coatedis about 27 cm². The buffer component 14 is placed in an oven at atemperature of about 100° C. or less, after the buffer coating isapplied, to dry the buffer coating by evaporating water from the buffercoating. Alternatively, the buffer component 14 may be dried inatmospheric air, rather than in the oven, though more drying time willbe required. The buffer coating is allowed to dry until the weight ofthe buffer component 14 remains steady.

As an alternative to use of the buffer coating, the pH buffering agentmay be heterogeneously dispersed in the absorbent material of the buffercomponent 14 in a number of different ways. For example, the absorbentmaterial of the buffer component 14 may be treated with the buffersuspension, after formation of the absorbent material into the layer(s)of the buffer component 14, to heterogeneously disperse the pH bufferingagent within the absorbent material.

When the pH buffering agent is incorporated into the absorbent materialusing the buffer suspension, there is typically no need to separatelyincorporate absorption aid into the absorbent material, when the carrieralso functions as absorption aid. However, when the carrier is orincludes water and does not include any of the materials that may serveas the hydrophilic agent (such as glycerine, and solutions ofpolyethylene glycol or polyethylene oxide, etc.), the absorbent materialshould incorporate or be treated with any absorption aid that is neededto make the absorbent material have the necessary absorptioncharacteristics described above, before applying the buffer suspensionto the absorbent material. Otherwise, the buffer suspension will not beabsorbed at a sufficient rate or to a sufficient extent in the absorbentmaterial.

The method of incorporating the pH buffering agent in the absorbentmaterial of the buffer component 14 using the buffer suspension involvesa number of steps. First, the carrier and the pH buffering agent aremixed together in a container to form the buffer suspension. As oneexample, when the carrier is glycerine and the pH buffering agent ision-exchange resin, such as the 50/50 weight ratio mixture of Amberlite®IRP-64 and IRP-88 copolymers, the weight ratio of the ion-exchange resinto the glycerine in the buffer suspension should be about 2.5 grams ofglycerine per gram of ion-exchange resin to attain the preferred ratioof 3.3 grams of the Amberlite® copolymer mixture per gram of reticulatedopen cell polyurethane foam when the buffer component 14 is made of a2.5 mm thick disk of the polyurethane foam with a diameter of about 4.1cm. These same results may be obtained by alternatively applying thebuffer suspension to a 2.5 mm thick sheet of the polyurethane foam thatis subsequently cut to form the 4.1 cm diameter polyurethane foam disks.Details about additional example compositions of the buffer suspensionare provided in Table 2. In Table 2, the pH buffering agent is the 50/50weight ratio mixture of Amberlite® IRP-64 copolymer and IRP-88 copolymermentioned above.

                  TABLE 2    ______________________________________                 Ratio of Weight of                              Ratio of Combined                 Substance (Grams)                              Weight of Substance                 to Weight of pH                              and Water (Grams)                 Buffering Agent                              to Weight of pH                 (Grams) In   Buffering Agent (Grams)    Substance    Buffer Suspension                              In Buffer Suspension    ______________________________________    Karaya Gum   about 1:5    about 6:1    (dry powder)    Polyvinyl Alcohol                 about 2:1    about 8:1    (MW ranges from about    30,000 to about 70,000    Daltons)    Polyethylene Glycol                 about 20:1   about 24:1    (MW is about 3,350    Daltons)    Polyethylene Oxide                 about 1:1    about 5:1    (MW is about 1,000,000    Daltons)    Carrageenan  about 1:6    about 7:1    (natural gelatin)    ______________________________________

After the buffer suspension is formed, the buffer suspension is thenapplied to the absorbent material of the buffer component 14 until theabsorbent material is saturated with the buffer suspension. Somesuitable techniques for applying the buffer suspension to the absorbentmaterial include spraying the absorbent material with the buffersuspension or soaking the absorbent material in the buffer suspension.When a layer of the absorbent material has a thickness of about 2.5 mm,the absorbent material typically needs to be soaked in the buffersuspension from about 1 minute to about 5 minutes to ensure that thebuffer suspension saturates the absorbent material.

The carrier is preferably selected so that, without additional stirringor agitation beyond that supplied on initial mixing, the pH bufferingagent remains substantially uniformly dispersed in the carrier and doesnot settle out in the carrier after being mixed with the carrier. Thissignificantly minimizes or eliminates the need for mixing during theapplication process and thereby simplifies the process of applying thebuffer suspension to the absorbent material. Selection of the carrier tomaintain uniform dispersion of the pH buffering agent in the carrierafter mixing is also believed to help attain uniform, or substantiallyuniform, dispersion of the pH buffering agent in the absorbent materialupon application of the buffer suspension to the absorbent material.Some examples of materials that may suitably serve as the carrierinclude glycerine; organic or aqueous solutions of polyethylene glycol,polyethylene oxide, polyvinyl alcohol, peptide-based gelatins, such ascarrageenan, and vegetable-based gums, such as karaya gum; and mixturesof these.

Alternatively, the carrier of the buffer suspension may consist of thepreviously mentioned mixture of dispersant and water. Examples ofsuitable dispersants include polycarboxylic acids, such aspolymethacrylates, including polymethacrylates available as Tamol®dispersants, Acusol® dispersants, and Acumer® dispersants from Rohm andHaas Co. Some particular examples of suitable Tamol® dispersants includeTamol® 850 dispersant and Tamol® 960 dispersant, and some particularexamples of suitable Acusol® dispersants include Acusol® 445 dispersantand Acusol® 445N dispersant.

After saturating the absorbent material of the buffer component 14 withthe buffer suspension, any excess of the buffer suspension is removedfrom the absorbent material by physical means. Examples of the physicalmeans used to remove excess amounts of the buffer suspension from theabsorbent material include squeezing, pressing, and wringing. Thecarrier is preferably selected to prevent the carrier from flowing oroozing out of the absorbent material after the physical means remove anyexcess of the buffer suspension from the absorbent material. Finally,the absorbent material that includes the dispersed pH buffering agent iswarmed in an oven at a temperature of about 100° C. or less, or inunheated air, to remove water from the layer(s) of the buffer component14. The component 14 is allowed to dry until the weight of the component14 remains steady.

Another technique for heterogeneously incorporating the pH bufferingagent in the absorbent material entails preparation of heterogeneous pHbuffering material, such as heterogeneous pH buffering foam orheterogeneous pH buffering gel. For absorbent material that is based ona resinous material, this technique generally entails (i) dispensing andmixing the ingredients (i.e. pH buffering agent, such as ion exchangeresin, and prepolymer(s) of the resinous material), (ii) blowing themixture to form heterogenous pH buffering foam, including incorporatinga blowing agent that is capable of promoting a blowing reaction, such asa creaming reaction, rising reaction, or a full rise reaction, and (iii)setting the foam, such as via a gelation reaction. Some representativeexamples of prepolymers of the resinous material for use in forming theheterogeneous pH buffering foam include polyvinylpyrrolidone prepolymer;polyvinyl alcohol prepolymer; polyethylene oxide prepolymer, polyacrylicacid prepolymer, polyethylene glycol prepolymer; and polyacrylamideprepolymer.

During preparation of the heterogeneous pH buffering foam, the rate ofthe blowing reaction and the rate of the gelation reaction aredetermined by catalyst that catalyzes the reaction. Examples of thecatalyst include tertiary amines, which promote blowing reactions, andorganometallics, which promote gelation reactions. Tertiary amines mayalso help enhance blowing reaction rate, and organometallics may alsohelp enhance gelation reaction rate. Additional blowing beyond thatattributable solely to the blowing reaction may be obtained byincorporating an auxiliary blowing agent, such as methylene chloride ora suitable chlorofluorocarbon, such as CFC-11. The use of asilicone-based surfactant will help selectively control cell size anduniformity in the foam by reducing surface tension of the foamingredients. The silicone-based surfactant may also enhancesolubilization of the foam ingredients.

Another example of a suitable procedure for preparing heterogeneous pHbuffering foam entails mixing any selected pH buffering agent, such asion-exchange material, with water to form an aqueous suspension.Preferably, the pH buffering agent is finely powdered to enhancedistribution of the pH buffering agent in the heterogeneous pH bufferingfoam and to enhance the surface area that is available for ion-exchange.The aqueous suspension is combined with prepolymer component(s) of thefoam with rapid stirring to form a foam mixture. Examples of theprepolymer component(s) useable in forming the heterogeneous pHbuffering foam include foamable polyurethane prepolymers that arederived from toluene diisocyanate and are marketed as part of the Hypol®group of products by W.R Grace & Company of Woburn, Mass. Some examplesof suitable Hypol® polyurethane prepolymers include Hypol® FHP 2000,Hypol® FHP 2002, and Hypol® FHP 3000 prepolymers.

After the aqueous suspension is combined with the prepolymercomponent(s), the foam mixture is further agitated until expansion dueto foaming subsides. The foam mixture is then subjected to a shapingprocess, such as extrusion, injection molding, compression molding,injection compression molding, or transfer molding, to form the layer(s)of the buffer component 14 and is subsequently cured. After formation,the polymer or copolymer foam and the ion-exchange resin that isdispersed within the foam form distinct phases of the heterogeneous pHbuffering foam.

In heterogeneous pH buffering foam, the pH buffering agent, such asion-exchange resin, is physically entrapped within the foam structure ofthe absorbent material. The heterogenous pH buffering foam should havean open cell structure that is capable of maintaining the electrolyticsolution as a confluent liquid throughout the buffer component 14. Theheterogenous pH buffering foam should also support enhanced movement ofany hydrogen or hydronium ions within the foam and thereby permit freecontact between the pH buffering agent and hydrogen or hydronium ions.

In another alternative, the pH buffering agent may be heterogeneouslydispersed in resinous or colloidal material prior to formation of thebuffer component 14 layer(s). For example, resinous material and pHbuffering agent may be uniformly combined in a suitable mixingcontainer. Next, the mixture of the resinous material and pH bufferingagent are melt-blended at a temperature that supports uniform dispersionof the pH buffering agent within the resinous material withoutdeleteriously affecting either the resinous material or the pH bufferingagent. After melt-blending is complete, the blended mixture of resinousmaterial and pH buffering agent is cooled to solidify the mixture. Themixture is then subjected to a shaping process, such as extrusion,injection molding, compression molding, injection compression molding,or transfer molding to form the layer(s) of the buffer component 14. Thelayer(s) of the buffer component 14 are subsequently cured.

Heterogeneous pH buffering hydrogel provides another alternative forheterogeneously dispersing pH buffering agent in the absorbent materialof the buffer component 14. Heterogeneous pH buffering gel may be formedby casting a mixture of the pH buffering agent, powdered gel particles,and water to form gel layer(s) of the buffer component 14. Somerepresentative examples of the colloidal material that may be used toform the gel of the heterogeneous pH buffering gel include variouspolysaccharides, such as pectin and starch, andpolyhydroxyethylmethacrylate.

The pH buffering reactions occurring in the anode and the cathode of theiontophoresis system, when pH buffering agent that is dispersed in thebuffer component 14 takes the form of ion-exchange material, may begenerally characterized as ion-exchange reactions. As noted, hydrogenions (H⁺) are evolved at the positive electrode (anode) and hydroxideions (OH⁻) are evolved at the negative electrode (cathode) byelectrolysis of water. Ion-exchange reactions occurring at the anodeneutralize hydrogen ions (H⁺) contained in the electrolytic solution andion-exchange reactions occurring at the cathode neutralize hydroxideions (OH⁻) contained in the electrolytic solution.

As an example, the ion-exchange reaction that occurs in the anode thathas the structure of the electrode 10, when the buffer component 14includes the ion-exchange copolymer of Formula II as the pH bufferingagent may be characterized according to reaction (1) as follows:

    --COOK+H.sup.+ →--COOH+K.sup.+,                     (1)

where --COOK represents one example of a suitable ion-exchangefunctionality of the ion-exchange copolymer and where --COOH representsthe carboxyl group. Additionally, H⁺ represents hydrogen ion generatedby electrolysis of water at the anode, and K⁺ represents potassium ionthat is released from the ion-exchange functionality by the ion-exchangereaction that neutralizes hydrogen ion (H⁺). Potassium ion (K⁺) is anexample of the adverse ion that is not intended for delivery into thehuman or animal body. Of course, it is be understood that theion-exchange functionality incorporated in the electrode 10 may be otherthan the --COOK functionality and that the ion released from theion-exchange functionality during the ion-exchange reaction in the anodemay be other than K⁺.

Where the ion-exchange reaction occurs in accordance with reaction (1),it has been found that potassium ions (K⁺) that are released by theion-exchange reaction into the electrolytic solution are about fivetimes less mobile than are hydrogen ions (H⁺). The decreased mobility ofpotassium ions supplements the enhanced delivery of medicament that isobserved by intentionally delivering most of the medicament ions usingthe medicament delivery component 12 and by placing the pH bufferingagent away from the component 12. Specifically, the undesirablecompetitive effect between the potassium ion and medicament ions to bedelivered to the body is significantly reduced, as compared to thecompetitive effect between hydrogen ion (H⁺) and the medicament ions tobe delivered to the body. Therefore, the efficiency of medicament iondelivery to the body is considerably improved when the --COOKfunctionality is incorporated in the buffer component 14 via theion-exchange copolymer. Furthermore, neutralization of the hydrogen ion(H⁺) makes it possible to maintain the pH at between about 4 and about 8in the electrolytic solution of the anode that is structured like theelectrode 10.

Though the ion-exchange functionality employed at the anode may be otherthan --COOK and though the adverse ion that is released from theion-exchange functionality may be other potassium ion (K⁺), theion-exchange functionality that is selected should release an ion thatis at least two times less mobile in the electrolytic solution thanhydrogen ion. Preferably, the ionic functionality is selected so thatthe ion released from the ion-exchange functionality has the samemobility or less mobility in the electrolytic solution than potassiumion.

The ion-exchange reaction that occurs in the cathode that is structuredlike the electrode 10, when the buffer component 14 includes theion-exchange copolymer of Formula I as the pH buffering agent, actuallyconsists of two separate reaction sequences that may be characterized asreaction (2) and reaction (3) as follows:

    --COOH+M.sup.+ →--COOM+H.sup.+                      (2)

    H.sup.+ +OH.sup.- →H.sub.2 O,                       (3)

In reaction (2), --COOH represents the ion-exchange functionality of theion-exchange copolymer included in the buffer component 14 of theelectrode 10 that serves as the cathode, and M⁺ represents metal ionreleased from the ionic substance in the medicament delivery component12 by dissociation of the ionic substance in the electrolytic solution.The metal ion (M⁺) depicted in reaction (2) that evolves on dissociationof the ionic substance is an example of the complimentary ion that isnot intended for delivery into the body. The metal ion released upondissociation of dexamethasone disodium phosphate, one example of theionic substance placed in the components 12, 14, is sodium ion (Na⁺),which is an example of M⁺ in equation (2).

Also, in reaction (2) and reaction (3), H⁺ represents the hydrogen ionreleased by the ionic functionality during reaction (2) and OH⁻represents the hydroxide ion generated by electrolysis of water at thecathode. Of course, it is to be understood that the ion-exchangefunctionality incorporated in the ion-exchange copolymer of the buffercomponent 14 in the cathode may be other than --COOH and that thecomplimentary ion released upon dissociation of the ionic substance inthe medicament delivery component 12 may be other than metal ion (M⁺).

The net result of reaction (2) and reaction (3) is that hydrogen ion(H⁺) released from the ionic functionality in the buffer component 14 ofthe cathode reacts with the hydroxide ion (OH⁻) generated byelectrolysis of water at the cathode to produce water (H₂ O). Since themetal ion (M⁺) that is dissociated from the ionic species exchanges withthe hydrogen ion H⁺ in reaction (2), the net effect of reaction (2) andreaction (3) is that no adverse or complimentary ion depicted inreaction (2) or reaction (3) remains in the electrolytic solution tocompete for delivery to the body with medicament ions.

An automated system for manufacturing the electrode 10 of the presentinvention is schematically depicted at 300 in FIG. 4. The system 300includes conveyers 310a, 310b, 310c, 310d, and 310e. Various componentsof the electrode 10 are individually prepared on individual ones of theconveyers 310a-310e. The conveyer 310a is also utilized for stacking andassembling the various components of the electrode 10. Specifically, atstation A, the release layer 28 is positioned on the conveyer 310a. Atstation B, the medicament delivery component 12 is positioned on therelease layer 28. At station C, the buffer component 14 is positioned onthe medicament delivery component 12. At station D, the conductivecomponent 16 is positioned on the buffer component 14. Finally, atstation E, the adhesive covering 20 is positioned over the release layer28, and components 12, 14, and 16. Plan views of the electrode 10components, as present at the stations A-E, are provided beneath theconveyor 310a at the respective stations A-E.

Though not depicted in FIG. 4, it is to be understood that the variouscomponents of the system 300 may be controlled by computers or otherlinking equipment to sequence the system 300 components for smooth,automated operations. The components 12, 14, and 16, as well as, theadhesive covering 20 and the release layer 28, that are formed using thesystem 300 may be any planar shape, such as circular, elliptical, andrectangular. However, the components 12, 14, 16, the adhesive covering20, and the release layer 28 are preferably rectangular, such as square,in shape when formed by the system 300 to minimize waste of thematerials used to form the components 12, 14, 16, the adhesive covering20, and the release layer 28.

The conveyers 310a-310e each include respective belts 311a-311e.Additionally, cutting mechanisms 312a-312e are individually associatedwith respective belts 311a-311e of conveyers 310a-310e. The cuttingmechanisms 312a-312e may be any mechanism or mechanisms that are capableof cutting web material. For example, the cutting mechanisms 312a-312emay be die cutters. As another example, the cutting mechanisms 312a-312emay be optical cutting mechanisms, such as lasers. When the cuttingmechanisms 312a-312e are die cutters, backing plates 313a-313e may beassociated with respective cutting mechanisms 312a-312e so that thebelts 311a-311e are disposed between the cutting mechanisms 312a-312eand respective backing plates 313a-313e. The backing plates 313a-313eprovide a support surface for the cutting mechanisms 312a-312e duringcutting operations.

The system 300 includes a roll 314 of the material that is used to formthe release layer 28. A web 316 of the material on the roll 314 isdispensed so that the web 316 travels between the cutting mechanism 312aand the belt 311a of the conveyer 310a. The cutting mechanism 312a thencuts a portion of the web 316 to make the release layer 28 of theelectrode 10. After the cutting mechanism forms the release layer 28,the remaining portion of the web 316 is lifted away from the conveyer311a, and the release layer 28 remains on the belt 311a, as at stationA.

The system 300 also includes a roll 318 of the absorbent material thatforms the medicament delivery component 12. A web 320 of the material onthe roll 318 is dispensed so that the web 320 travels between thecutting mechanism 312b and the belt 311b of the conveyer 310b. Thecutting mechanism 312b then cuts a portion of the web 320 to make themedicament delivery component 12. The remaining portion of the web 320is then lifted away from the belt 311b, and the cut web portion, in theform of the medicament delivery component 12, is deposited on the belt311b. The conveyer 310b then deposits the medicament delivery component12 on the release layer 28 at station B of the conveyer 310a.

The system 300 also includes a roll 322 of the absorbent material thatis used to form the buffer component 14. A web 324 of the roll 322absorbent material is dispensed so that the web 324 travels between thecutting mechanism 312c and the belt 311c. The cutting mechanism 312ccuts a portion of the web 324 to make the buffer component 14. Theremaining portion of the web 324 is then lifted away from the belt 311a,and the cut web portion, in the form of the buffer component 14, isdeposited onto the belt 311c. The conveyer 310c subsequently depositsthe web portion 14 onto the medicament delivery component 12 at stationC on the conveyer 310a.

The system 300 additionally includes a roll 326 of the material that isused to form the conductive component 16. A web 328 of the roll 326material is dispensed so that the web 328 travels between the cuttingmechanism 312d and the belt 311d. The cutting mechanism 312d cuts aportion of the web 328 to make the conductive component 16. The cuttingmechanism 312d additionally cuts an aperture 329 in the conductivecomponent 16 for receiving the conductive terminal 18. The remainingportion of the web 328 is then lifted away, and the cut portion of theweb 328, in the form of the conductive component 16, is dropped onto thebelt 311d. The conveyer 310d then deposits the conductive component 16onto the buffer component 14 at station D on the conveyer 310a.

The system 300 further includes a roll 330 of the material that is usedto form the adhesive covering 20 of the electrode 10. A web 332 of theroll 330 material is dispensed so that the web 332 travels between thecutting mechanism 312e and the belt 311e. The cutting mechanism 312ethen cuts a portion of the web 332 to form the adhesive covering 20. Thecutting mechanism 312e also cuts an aperture 333 in the adhesivecovering 24 for receiving the conductive terminal 18. Thereafter, theremaining portion of the web 332 is lifted away from the belt 311e, andthe cut portion of the web 332, in the form of the adhesive covering 20,drops to the belt 311e. The conveyer 310e then deposits the adhesivecovering onto the conductive component 16 at station E on the conveyer310a.

Though not depicted in FIG. 4, it is to be understood that the conveyer310d may also include a structure (not shown) for positioning theconductive terminal 18 within the aperture 329 of the conductivecomponent 16 after the cutting mechanism 312d cuts the aperture 329.Additionally, though not depicted in FIG. 4, it is to be understood thatthe system 300 may be configured to insert the conductive terminal 18that is associated with the conductive component 16 within the aperture333 that is cut in the adhesive covering 20. Additionally, though notdepicted in FIG. 4, the system 300 preferably further includes apressing station (not shown) for adhesively securing the adhesivecovering 20 to the conductive component 16, to portions of themedicament delivery component 12 that face the adhesive covering 20 andwhich are not covered by the buffer portion 14, and to portions of therelease layer 28 that face the adhesive covering 20 and which are notcovered by the medicament delivery component 12.

An alternative system for making the electrode 10 is depicted at 400 inFIG. 5. The system 400 includes all of the features and detailspossessed by the system 300 of FIG. 4. Furthermore, the system 400 ofFIG. 5 contains additional equipment for making the medicament deliverycomponent 12 and the buffer component 14.

Specifically, the system 400 includes an apparatus 410 for saturatingthe portion of the web 320 that is to be cut by the mechanism 312b withabsorption aid, such as the hydrophilic agent. The apparatus 410 maytake the form of a sprayer 412 that sprays the hydrophilic agent on theweb 320. Though not depicted in FIG. 5, the apparatus 410 may include apair of sprayers 412 located on opposing sides of the web 320.Alternatively, the apparatus 410 may take the form of any other suitableequipment for saturating the web 320 with the hydrophilic agent,including, but not limited to, an apparatus (not shown) that permits theweb 320 to be dipped in a pool (not shown) of the hydrophilic agent. Thesystem 400 also includes a mechanism 414, such as a pair of rollers 416located on opposing sides of the web 320, for squeezing excesshydrophilic agent out of the portion of the web 320 that is saturatedwith the hydrophilic agent by the apparatus 410.

The system 400 also includes an apparatus 418 for saturating the portionof the web 324 that is to be cut by the mechanism 312c with the buffersuspension of the pH buffering agent and the carrier. The apparatus 418may take the form of a sprayer 420 that sprays the buffer suspension onthe web 324. Though not depicted in FIG. 5, the apparatus 418 mayinclude a pair of sprayers 420 located on opposing sides of the web 324.Alternatively, the apparatus 418 may take the form of any other suitableequipment for saturating the portion of the web 324 that is to be cutwith the buffer suspension, including, but not limited to, an apparatus(not shown) that permits the web 324 to be dipped in a pool (not shown)of the buffer suspension. The system 400 also includes a mechanism 422,such as a pair of rollers 424 located on opposing sides of the web 324,for squeezing excess buffer suspension out of the portion of the web 324that is saturated with the buffer suspension by the apparatus 418.

Though FIG. 5 depicts the system 400 as including the apparatus 410 andassociated rollers 416, along with the apparatus 418 and associatedrollers 424, it is to be understood that the system 400 may exclude theapparatus 410 and associated rollers 416 and/or the apparatus 418 andassociated rollers 424. The system 400 may exclude the apparatus 410 andthe associated rollers 416 when the absorbent material on the roll 318has the absorbent characteristics required for the component 12 that areprovided above. The system 400 may exclude the apparatus 418 andassociated rollers 424 when the absorbent material on the roll 322includes heterogeneously dispersed pH buffering agent or the buffercoating and therefore does not require application of the buffersuspension that is dispensed by the apparatus 418.

Returning to FIG. 4, though not depicted, it is to be understood thatthe system 300 may include the apparatus 418 for saturating the portionof the web 324 that is to be cut by the mechanism 312c with the buffersuspension of the pH buffering agent and the carrier, along with theassociated rollers 424. The system 300 would include the apparatus 418and associated rollers 424 when the absorbent material on the roll 322does not already incorporate pH buffering agent and therefore requiresapplication of the buffer suspension that is dispensed by the apparatus418.

When the apparatus 418 is employed in the system 300, the apparatus 418may alternatively include a pair of sprayers 420 located on opposingsides of the web 324. Alternatively, the apparatus 418 that may be usedin the system 300 may take the form of any other suitable equipment forsaturating the portion of the web 324 that is to be cut with the buffersuspension, including, but not limited to, an apparatus (not shown) thatpermits the web 324 to be dipped in a pool (not shown) of the buffersuspension.

Continuing with FIG. 5, though not depicted, it is to be understood thatan apparatus (not shown) similar to the apparatus 410 may be associatedwith the web 324 for saturating the portion of the web 324 that is to becut by the mechanism 312c with hydrophilic agent. The apparatus forsaturating the portion of the web 324 may take the form of the sprayer412 that sprays the hydrophilic agent on the web 324. The apparatus forsaturating the portion of the web 324 with hydrophilic agent, along withthe associated equipment for squeezing excess hydrophilic agent out ofthe web 324, should be positioned upstream of the equipment 418 forsaturating the web 324 with the buffer suspension so that thehydrophilic agent has been applied and excess hydrophilic agent has beenremoved prior to application of the buffer suspension.

Though not depicted in FIG. 5, the apparatus associated with the web 324for saturating the web 324 with hydrophilic agent, similar to theapparatus 410 associated with the web 320, may include a pair ofsprayers 412 that are located on opposing sides of the web 324.Alternatively, the apparatus associated with the web 324 may take theform of any other equipment that is capable of saturating the portion ofthe web 324 to be cut with hydrophilic agent, including, but not limitedto, an apparatus (not shown) that permits the web 324 to be dipped in apool (not shown) of the hydrophilic agent.

The system 300 of FIG. 4 for making the electrode 10 may be modified toform a system that is depicted in FIG. 6 at 500 for making the electrode110. The system 500 is similar to the system 300 of FIG. 4, with someexceptions. First, the system 500 of FIG. 6 does not include theconveyer 310d, the cutting mechanism 312d, the backing plate 313d, orthe roll 326 that are used to make the conductive component 16.Furthermore, in the system 500, the conveyer 310c, the cutting mechanism312c, the backing plate 313c, and the roll 322 are used to make thebuffer component 114, rather than the buffer component 14 depicted inFIG. 4. To make the buffer component 114 in the system 500 of FIG. 6,the roll 322 absorbent material incorporates the conductive filler thatis effective to make the buffer component 114 conductive. Other than theconductive filler, the material included on the roll 322 in the system500 has the same composition as the material on the roll 322 that isincluded in the system 300.

The portion of the web 324 that is cut by the cutting mechanism 312c inthe system 500 takes the form of the buffer component 114. After thebuffer component 114 is cut from the web 324, the conveyer 310c depositsthe buffer component 114 on the medicament delivery component 12 atstation C on the conveyer 310a. Thereafter, the conveyer 310e depositsthe adhesive covering 20 that is cut from the web 332 on the buffercomponent 114 at station E on conveyer 310a.

Though not depicted in FIG. 6, the conveyer 310e of the system 500 mayalso include a structure (not shown) for positioning the conductiveterminal 18 within the aperture 333 that is cut in the adhesive covering20. Also, though not depicted, the system 500 preferably furtherincludes a pressing station (not shown) for adhesively securing theadhesive covering 20 to the buffer component 114, to portions of themedicament delivery component 12 facing the adhesive covering 20 thatare not covered by the buffer portion 114, and to portions of therelease layer 28 facing the adhesive covering 20 that are not covered bythe medicament delivery component 12.

Though not depicted in FIG. 6, it is to be understood that the system500 may include the apparatus 418 for saturating the portion of the web324 that is to be cut by the mechanism 312c with the buffer suspensionof the pH buffering agent and the carrier, along with the associatedrollers 424. When the apparatus 418 is employed in the system 500, theapparatus 418 may include a pair of sprayers 420 located on opposingsides of the web 324. Alternatively, the apparatus 418 that may be usedin the system 500 may take the form of any other suitable equipment forsaturating the portion of the web 324 that is to be cut with the buffersuspension, including, but not limited to, an apparatus (not shown) thatpermits the web 324 to be dipped in a pool (not shown) of the buffersuspension.

Another system for making the electrode 10 is depicted at 600 in FIG. 7.The system 600 includes all of the features and details possessed by thesystem 500 of FIG. 6. Furthermore, the system 600 of FIG. 7 may includeadditional equipment for making the medicament delivery component 12 andthe buffer component 114 out of absorbent material. Specifically, thesystem 600 may include the apparatus 410, that was described in thecontext of the system 400, for saturating the portion of the web 320that is to be cut by the mechanism 312c with the hydrophilic agent. Thesystem 600 may include the mechanism 414 that was described in thecontext of the system 400 for squeezing excess hydrophilic agent out ofthe portion of the web 320 that is saturated with the hydrophilic agentby the apparatus 410. All details prescribed for the apparatus 410 andthe mechanism 414 in the context of the system 400 also apply to theapparatus 410 and the mechanism 414 that may be included in the system600.

The system 600 may also include the apparatus 418 that was described inthe context of the system 400 for saturating the portion of the web 324that is to be cut by the mechanism 312c with the buffer suspension ofthe pH buffering agent and the carrier. The system 600 may also includethe mechanism 422 described in the context of the system 400 forsqueezing excess buffer suspension out of the portion of the web 324that is saturated with the buffer suspension by the apparatus 418. Alldetails prescribed for the apparatus 418 and the mechanism 422 in thecontext of the system 400 also apply to the apparatus 418 and themechanism 422 that may be included in the system 600.

Though the system 600 may include the apparatus 410 and associatedrollers 416, along with the apparatus 418 and associated rollers 424, itis to be understood that the system 600 may also exclude the apparatus410 and associated rollers 416 and/or the apparatus 418 and associatedrollers 424. The system 600 may exclude the apparatus 410 and theassociated rollers 416 when the absorbent material on the roll 318 hasthe absorbent characteristics required for the component 12 that areprovided above. The system 600 may exclude the apparatus 418 andassociated rollers 424 when the absorbent material on the roll 322includes heterogeneously dispersed pH buffering agent or the buffercoating and therefore does not require application of the buffersuspension that is dispensed by the apparatus 418.

Though not depicted in FIG. 7, it is to be understood that the system600 may include an apparatus (not shown) similar to the apparatus 410for saturating the portion of the web 324 that is to be cut by themechanism 312c with hydrophilic agent. The apparatus for saturating theportion of the web 324 may take the form of the sprayer 412 that spraysthe hydrophilic agent on the web 320. The apparatus for saturating theportion of the web 324 with hydrophilic agent, along with the associatedequipment for squeezing excess hydrophilic agent out of the web 324should be positioned upstream of the equipment 318 for saturating theweb 324 with the buffer suspension so that the hydrophilic agent hasbeen applied and excess hydrophilic agent has been removed prior toapplication of the buffer suspension.

Though not depicted in FIG. 7, it is to be understood that the apparatusassociated with the web 324 for saturating the web 324 with hydrophilicagent, similar to the apparatus 410 associated with the web 320, mayinclude a pair of sprayers 412 that are located on opposing sides of theweb 324. Alternatively, the apparatus associated with the web 324 maytake the form of any other equipment that is capable of saturating theportion of the web 324 to be cut with hydrophilic agent, including, butnot limited to, an apparatus (not shown) that permits the web 324 to bedipped in a pool (not shown) of the hydrophilic agent.

Though not depicted in FIGS. 4-7, it is to be understood that thesystems 600 may be modified to make the electrode 210 of FIG. 3 byincluding an additional conveyor (not shown) and conveyor belt (notshown) prior to the conveyor 310b with an associated roll and web of thewicking layer 212. This additional conveyor, conveyor belt, roll, andweb would be positioned above the equipment at station A for forming therelease layer 28 so that the wicking layer 212 is deposited on therelease layer 28 at the station B. The equipment depicted at station Bfor forming the medicament delivery component 12 would be shifted sothat the medicament delivery component is deposited onto the wickinglayer 212, instead of the release layer 28. The remaining equipmentdepicted in or described with respect to FIGS. 4-7 for producing theremaining components (buffer component 14 and conductive component 16 orbuffer component 114) and elements (adhesive covering 20 and conductiveterminal 18) would be shifted to remain downstream of the equipment forforming the medicament delivery component 12 in the same relation to theequipment for forming the medicament delivery component 12 that isdepicted in FIGS. 4-7.

In practice, use of the iontophoresis system that includes the cathodeand/or the anode, either or both of which are structured like theelectrode 10, is efficient and convenient. Where the active electrode ofthe iontophoresis system is structured like the electrode 10, theelectrolytic solution containing the medicament ions may be injectedinto the component 12 or the component 14 of the electrode 10 afterformation of the electrode 10 using any conventional technique, such aswith a hypodermic syringe. Medicament ions that will be delivered to thebody are typically included in the electrolytic solution by dissociatingthe ionic substance of interest in the appropriate solvent before theelectrolytic solution is injected into the component 12 or 14. Forelectrodes that will not be used to iontophoretically deliver medicamentions, electrolytic solution that includes conductive ions other thanmedicament ions may be injected into the component 12 or the component14 of the electrode 10 after formation of the electrode 10 using anyconventional technique, such as with the hypodermic syringe.Furthermore, as already explained, different medicament ions may beplaced in the different electrolytic solutions that are placed in themedicament delivery components 12 of the cathode and the anode, forsimultaneous iontophoretic delivery from both the cathode and the anode.

Next, both of the electrodes of the iontophoresis system are attached tothe surface of the body, such as the skin of the patient. For anyelectrode of the iontophoresis system that is structured like theelectrode 10, the component 12 faces, and is placed in contact with, theskin after the release layer 28 is removed. Additionally, the terminal18 faces away from the skin, and the adhesive cover 20 is attached tothe skin, after the release layer 28 is removed, to secure the electrode10 to the body. If the return electrode of the iontophoresis system isstructured like the electrode 10, the terminal 18 of the electrode 10 isconnected to the source of electrical power to support current flowthrough the body. If the active electrode of the iontophoresis system isstructured like the electrode 10, the terminal 18 of the electrode 10 isconnected to the source of electrical power to initiate delivery ofmedicament ions into the body.

It should also be understood that the anode and the cathode may beconnected to the source of electrical power such that the iontophoresissystem that includes the anode structured like the electrode 10 and/orthe cathode structured like the electrode 10 is capable of providingsuitable current flow to the body to stimulate a muscle of the body. Inthis application, the medicament delivery component 12 may includeelectrolytic solution that includes medicament ions, if delivery ofmedicament ions will coincide with muscle stimulation. Alternatively,the medicament delivery component 12 may include electrolytic solutionthat is free of medicament ions and that includes conductive ions, ifdelivery of medicament ions will not coincide with muscle stimulation.In the case of muscle stimulation alone, the current source would supplyan appropriate current form, such as alternating current.

The present invention is more particularly described in the followingExamples which are intended as illustrations only since numerousmodifications and variations within the scope of the general formulationwill be apparent to those skilled in the art.

EXAMPLE 1

Example 1 demonstrates the process of incorporating the pH bufferingagent into the absorbent material of the buffer component 14 using thebuffer suspension of pH buffering agent dispersed in the carrier. Inthis Example, the pH buffering agent was a mixture of about 50% byweight Amberlite® IRP-64 copolymer and about 50% by weight Amberlite®IRP-88 copolymer. The carrier of the buffer suspension in this Examplewas glycerine. The absorbent material of the buffer component 14 in thisExample was Foamex PREMIUM reticulated, fine pore, polyurethane foamthat is available from Foamex, Inc. of Eddystone, Pa.

The Foamex PREMIUM polyurethane foam used in this Example had an averagepore density of about 70 to about 80 pores per linear inch (ppi) ofpolyurethane foam surface and an average pore diameter ranging fromabout 200 micrometers to about 240 micrometers. The Foamex PREMIUMpolyurethane foam was shaped like a disk. The foam disk was 2.5 mm thickand had a diameter of about 4.1 cm. The surface area of the foam diskwas about 13.2 cm² and the foam disk weighed about 0.09 grams.

The goal of Example 1 was to incorporate about 3.3 grams of Amberlite®copolymer mixture per gram of Foamex PREMIUM polyurethane foam in theindividual foam disks. Since each foam disk of this Example weighedabout 0.09 grams prior to treatment with the buffer suspension, it wasdesired to incorporate about 0.3 grams of the Amberlite® copolymermixture into each foam disk. 0.3 grams of the Amberlite® copolymermixture permits the buffer component 14 to hold about 0.5milliequivalents of acid and about 0.5 milliequivalents of base during a40 minute period of iontophoretic medicament ion delivery, whilemaintaining a pH in the range of about 4 to about 8 in the electrolyticsolution of the electrode 10. 0.5 milliequivalents of acid is about fivetimes the amount of H⁺ ions that would be expected to be formed byelectrolysis of water at the electrode 10 serving as the anode during 40minutes of iontophoresis at an applied current of 4 mA, and 0.5milliequivalents of base is about five times the amount of OH⁻ ions thatwould be expected to be formed by electrolysis of water at the electrode10 serving as the cathode during 40 minutes of iontophoresis at anapplied current of 4 mA.

In this Example, three different weight ratios of glycerine to resin(Amberlite® copolymer mixture) were used in the forming the buffersuspension. In one buffer suspension, the weight ratio of glycerine toresin was about 2.5 grams of glycerine per gram of Amberlite® copolymermixture. In another of the buffer suspensions, the glycerine to resinratio was about 4 grams of glycerine per gram of Amberlite® copolymermixture. In the third buffer suspension, the glycerine resin ratio wasabout 5.8 grams of glycerine per gram of Amberlite® copolymer mixture.

In this Example, 132 of the foam disks were saturated with the buffersuspension having the glycerine to resin weight ratio of about 2.5, atleast 20 of the foam disks were saturated with the buffer suspensionhaving the glycerine to resin weight ratio of about 4, and at least 20of the foam disks were saturated with the buffer suspension having theglycerine to resin weight ratio of about 5.8. The mean weight of eachfoam disk was determined to be 0.092 grams±0.003 grams prior to beingsaturated with the buffer suspension.

The foam disks were impregnated with the pH buffering agent by dippingeach foam disk in the buffer suspension for a period of about 2 minutesto ensure saturation of the foam disks with the buffer suspension. Thefoam disks were then removed from the buffer suspension and wereindividually wrung out between two rollers that were separated from eachother by about 2 mm to remove excess buffer suspension from the foamdisks.

The foam disks were each individually weighed after removal of excessbuffer suspension using the rollers. Based on the difference between theweight of the individual foam disks before application of the buffersuspension and the weight of the respective foam disks after saturationwith and removal of excess buffer suspension, the weight of buffersuspension added to each foam disk following the dipping and wringingprocess was calculated. The weight of buffer suspension added to thefoam disks versus the weight ratio of glycerine to resin in the buffersuspension is graphically presented in FIG. 8. From the plot of FIG. 8,it was determined that the weight of buffer suspension incorporated ineach foam disk is a polynomial function of the glycerine to resin weightratio in the buffer suspension.

For each foam disk, the weight of buffer suspension incorporated pergram of foam in the foam disk was then calculated. The results of thesecalculations are presented graphically in FIG. 9 as a function of theweight ratio of glycerine to resin in the buffer suspension. The datathat are plotted in FIG. 9 demonstrate that the individual foam disksare capable of incorporating the buffer suspension in an amount that isequal to about 13 times the dry weight of the individual foam disks.

The amount of Amberlite® copolymer mixture that remained in each foamdisk after the foam disk was wrung out was then calculated based on theglycerine to resin weight ratios of the different buffer suspensions. Inthis calculation, it was assumed that the process of absorbing thebuffer suspension into the foam disks along with the process of removingexcess buffering suspension from the foam disks using the rollers didnot effect the glycerine to resin weight ratio of the buffer suspensionthat was incorporated in the foam disks. This assumption is based on thebelief that any filtering effect of the disk foam upon particles ofAmberlite® copolymer is negligible. This belief is thought to bereasonable considering that the average pore size of the Foamex PREMIUMfoam is about 200 micrometers to about 240 micrometers, while theparticles of the Amberlite® copolymers range in size from about 25micrometers to about 150 micrometers. This assumption is also based onthe belief that the glycerine to resin weight ratio in the buffersuspension was the same throughout the dipping operation. This belief isthought to be reasonable considering that no settling of Amberlite®copolymer from the glycerine was observed in the containers that heldthe various buffer suspensions.

The calculated weight of Amberlite® copolymer incorporated per gram ofFoamex PREMIUM foam in the foam disk, versus the weight ratio ofglycerine to resin in the buffer suspension, is graphically presented inFIG. 10. FIG. 10 demonstrates that the buffer suspension with theglycerine to weight ratio of about 2.5 is needed to attain the desiredratio of 3.3 grams of Amberlite® copolymer mixture per gram of FoamexPREMIUM foam in the foam disk of the component 14 when the component 14is made of a 2.5 mm thick disk of open cell polyurethane foam that has adiameter of about 4.1 cm. The buffer suspension with the glycerine toresin weight ratio of about 4 was only capable of forming the foam diskswith a ratio of about 1.2 grams of Amberlite® copolymer mixture per gramof foam, whereas the buffer suspension with the glycerine to resinweight ratio of about 5.6 was only capable of attaining a ratio of about0.6 grams of Amberlite® copolymer mixture per gram of foam in the foamdisk.

The data obtained by impregnating the 132 different foam disks with thebuffer suspension having the glycerine to resin weight ratio of about2.5 confirms the conclusions reached based on the data of FIG. 10.Statistical data obtained from the 132 different foam disks impregnatedwith the buffer suspension having the glycerine to weight ratio of about2.5 are presented in Table 3:

                  TABLE 3    ______________________________________              Grams of Buffer                             Grams of Amberlite ®              Suspension Per Gram                             Copolymer Mixture Per              of Foam in Foam                             Gram of Foam in Foam    Statistical Data              Disk           Disk    ______________________________________    Mean      11.45          3.28    Std. Dev. 0.70           0.20    Minimum   9.90           2.83    Maximum   12.94          3.70    ______________________________________

TEST EQUIPMENT AND METHODS USED IN EXAMPLES 2-5 AND COMPARATIVE EXAMPLES1-6

Examples 2-5 and Comparative Examples 1-6 simulate in vivo iontophoresistreatment using iontophoresis electrodes made of different materials andstructured differently. Examples 2-3 and Comparative Examples 1-4simulate iontophoretic delivery of dexamethasone phosphate. Example 4and Comparative Example 5 simulate iontophoretic delivery of protonatedlidocaine, and Example 5 and Comparative Example 6 simulateiontophoretic delivery of minoxidil base.

The test equipment used to simulate in vivo iontophoresis treatment inExamples 2-5 and Comparative Examples 1-6 is depicted at 700 in FIG. 11.The equipment 700 included a three-compartment diffusion cell 710 thatprovided conditions closely simulating those present during actual invivo iontophoresis treatment. The cell 710 included a receptorcompartment 712 that was filled with saline solution. The salinesolution was a solution of water that included 0.9 weight % sodiumchloride.

The cell 710 also included a donor compartment 714 and a returncompartment 716. In Examples 2-5 and Comparative Examples 1-6, the donorcompartment 714 was the electrode under consideration in the particularExample or Comparative Example. The receptor component 716 included acarbon film 718 that was attached in electrical communication to aconductive karaya gum pad 720. The donor compartment 714 included aconductive terminal 722, such as a conductive snap connector of theelectrode under consideration in the particular Example or ComparativeExample, and the return compartment 716 included a conductive terminal724 that was attached in electrical communication to the carbon film 718and the conductive karaya pad 720.

The cell 710 also included a hairless mouse skin 726 that was positionedbetween and in contact with the receptor compartment 712 and the donorcompartment 714. The cell 710 further included a hairless mouse skin 728that was positioned between and in contact with the receptor compartment712 and the conductive karaya pad 720 of the return compartment 716. Thehairless mouse skins were obtained from Charles River Laboratory ofWilmington, Mass. The hairless mouse skins 726, 728 each included afresh whole thickness of mouse skin with both epidermal and dermallayers. New hairless mouse skins were used as the skins 726, 728 foreach replicate of each Example and Comparative Example. In the cell 710,the skins 726, 728 were stretched taught and secured in place by teflonholders (not shown) with the dermal sides of the mouse skins positionedagainst the receptor compartment 712.

The cell 710 was sized to ensure that the effective skin 726 surfacearea available for medicament ion transport from the compartment 714 tothe compartment 712 matched the size and shape of the effective deliveryarea of the electrode being tested in the particular Example orComparative Example. The effective delivery area of the particularelectrode being tested was defined as the area of the receptorcompartment 714 surface that was in contact with the mouse skin 726. Allin vivo simulations were conducted at room temperature with continuousstirring of the solution in the receptacle compartment 712. In each ofthe Examples and Comparative Examples, the number of experimentalreplicates was at least 10.

During each simulation, the iontophoresis electrode under considerationwas filled to capacity with medicament ion solution prior to the startof the simulation. The conductive terminal 722 of the donor compartment714 and the conductive terminal 724 of the receptor compartment 724 wereeach attached to a galvanostatic power supply 730. The galvanostaticpower supply 730 was a Model 273A potentiostat/galvanostat that isavailable from EG&G Princeton Applied Research of Princeton, N.J.Depending upon the ionic state of the medicament ion employed in thedonor compartment 714, a constant current of either +4 mA or -4 mAcurrent was applied to the donor compartment 714 for a period of 40minutes in each of the replicates of Examples 2-5 and ComparativeExamples 1-6.

Voltage drop across the hairless mouse skins 726, 728 could not beaccurately measured at reasonable cost. Therefore, the voltage dropacross the cell 710 between the conductive connectors 722 and 724 wasmonitored instead. The measured voltage drop across the cell 710 duringExamples 2-5 and Comparative Examples 1-6 generally ranged between about7 and 15 volts. Significant variations were noticed even among replicateexperimental runs. These variations are believed to be due to thebiological nature of the hairless mouse skin and due to differences inskin resistance from mouse to mouse.

The dexamethasone sodium phosphate used in Examples 2-3 and ComparativeExamples 1-4 and the lidocaine hydrochloride used in Example 4 andComparative Example 5 were obtained from Paddock Laboratory ofMinneapolis, Minn. The minoxidil base used in Example 5 and ComparativeExample 6 was obtained from Drs. Pedro Huerta, Lloyd Allen, and VilasPrahbu of the University of Oklahoma College of Pharmacy in OklahomaCity, Okla. The medicament ion solutions used in the various electrodesin Examples 2-5 and Comparative Examples 1-6 were prepared using eitherhigh pressure liquid chromatograph-grade water obtained from Burdick &Jackson of Muskegon, Mich. or deionized water having a resistancegreater than 18 MΩ that was obtained from a Barnstead E-PURE system. TheBarnstead E-PURE system is available from the Barnstead Company ofBoston, Mass.

The amount of medicament ions transferred into the receptor compartment712 during the various Examples and Comparative Examples was determinedat approximately 5 minute intervals during the 40 minute iontophoresisperiod using High Pressure Liquid Chromatography (HPLC). Medicament ionconcentrations in the receptor compartment 712 solution were determinedusing 100 μL samples. To maintain a constant volume of the receptorcompartment 712 solution, each withdrawn aliquot volume was replacedwith an equal volume of 0.9 weight percent saline solution.

The concentration of the particular medicament ion under considerationin the various simulations of the particular Examples and ComparativeExamples was determined from the receptor compartment 712 solutionsample using HPLC. The High Pressure Liquid Chromatography systememployed a Waters 501 HPLC pump and a Waters 440 absorbance detectorthat are available from Waters Corp. of Milford, Mass. Peak height datawas collected using Millennium 2010 software that is available fromWaters Corp.

The HPLC analysis of dexamethasone phosphate in the sample of receptorcompartment 712 solution was conducted with a Waters μBondapak C₁₈ (3.9mm×300 mm) exclusion column obtained from Waters Corp. of Milford, Mass.The mobile phase of the HPLC system during dexamethasone phosphatedeterminations was a solution of 60 weight % methanol and 40 weight %water that contained 20 mM potassium phosphate monobasic and had a pH ofabout 4.2. Ultraviolet light with a wavelength of 254 nanometers wasused for detection. The flow rate of the receptor compartment 712solution sample in the HPLC system was set at 2.0 ml/minute so that theretention time of dexamethasone phosphate in the HPLC system was about3.5 minutes.

The HPLC analysis of protonated lidocaine in the sample of receptorcompartment 712 solution was conducted with a Waters μNovapak C₁₈ (3.9MM×150 MM) exclusion column obtained from Waters Corporation. The mobilephase of the HPLC system was a solution with a pH of about 3 thatcontained 53.6 weight % acetonitrile, 43.8 weight % water, 1.9 weight %triethylamine, and 0.7 weight % phosphoric acid. Ultraviolet light witha wavelength of 254 nm was used to detect the protonated lidocaine. Theflow rate of the receptor compartment 712 solution sample in the HPLCsystem was set at 1.0 ml/min so that the retention time of protonatedlidocaine in the HPLC system was about 2.7 minutes.

The HPLC analysis of minoxidil base in the sample of receptorcompartment 712 solution was conducted with a Waters μBondapak C₁₈ (3.9mm×300 mm) exclusion column obtained from Waters Corporation. The mobilephase of the HPLC system was a solution of 60 weight % methanol and 40weight % water that contained 20 mM potassium phosphate monobasic andhad a pH of about 4.2. Ultraviolet light with a wavelength of 254nanometers was used to detect the minoxidil base. The flowrate of thereceptor compartment 712 solution sample in the HPLC system was set at2.5 ml/min so that the retention time of minoxidil base in the HPLCsystem was about 3.0 minutes.

DATA ANALYSIS TECHNIQUES USED IN EXAMPLES 2-5 AND COMPARATIVE EXAMPLES1-6

The transport behavior for medicament ions moving from the donorcompartment 714 into the receptor compartment 712 for each of thedifferent Examples and Comparative Examples was assessed by plotting thecumulative amount (μg) of medicament ion delivered into the receptorcompartment 12 as a function of the applied charge (mA.min). Thecumulative amount of medicament ion delivered per unit of effectivedelivery area of the donor compartment 714 was also plotted as afunction of time to perform further detailed analysis of the transportbehavior data.

The steady state flux of medicament ions into the receptor compartment712 was calculated by determining the slope of the linear portion of theplot of cumulative amount of delivered medicament ion per unit ofeffective delivery area versus time, by linear regression analysis.Thus, the steady state flux calculation took into account the lag time,which is the time required for the medicament ions to penetrate themouse skin at the beginning of the iontophoresis simulation. The lagtime corresponds to the time during which the steady state flux into thereceptor compartment 712 is 0. The lag time was determined by firstextrapolating the linear portion of the plot to the time axis and thenmeasuring the period between time 0 and the point where the extrapolatedline intercepted the time axis.

DESCRIPTION OF DONOR ELECTRODES USED IN EXAMPLES 2-5 AND COMPARATIVEEXAMPLES 1-6

The iontophoresis electrode used in Examples 2, 4, and 5 was theelectrode 210 that is depicted in FIG. 3. In the electrode 210 used inExamples 2, 4, and 5, the conductive component 16 was a thin carbonfilm, and the medicament delivery component 12 was a disk of AMREL™ 6polyurethane foam that is available from the Kenn-Med Division of Rynel,Ltd., Inc of Boothbay, Me. The AMREL™ 6 polyurethane foam disk was about3 mm thick and had a diameter of about 4.1 cm. The AMREL™ 6 polyurethanefoam used in these Examples as the component 12 had an average poredensity ranging from about 50 to about 200 pores per linear inch (ppi)of the polyurethane foam surface and an average pore diameter rangingfrom approximately 150 micrometers to approximately 350 micrometers. Thecontact area between the wicking layer 212, which is equivalent to thereceptor compartment 714 surface in Examples 2, 4, and 5, and the mouseskin 726 was about 22 cm², based on the about 5.3 cm diameter of thewicking layer 212. Thus, the effective delivery area of the electrode210 for medicament ion delivery was about 22 cm².

The buffering component 14 of the electrode 210 used in Examples 2, 4,and 5 was a disk of Foamex PREMIUM polyurethane foam that incorporatedthe pH buffering agent. The foam disk was about 2.5 mm thick and had adiameter of about 4.1 cm. The Foamex PREMIUM foam used in these Exampleshad an average pore density of about 70 to about 80 pores per linearinch (ppi) of the polyurethane foam surface and an average pore diameterranging from approximately 200 micrometers to approximately 240micrometers.

The foam disk of the buffering component 14 included pH buffering agentthat was incorporated into the foam of the disk using the buffersuspension of pH buffering agent dispersed in the carrier. In Examples2, 4, and 5, the foam disk of the buffer component 14 had a weight ofabout 0.9 grams, prior to incorporation of the buffer suspension intothe disk. About 0.3 grams of the pH buffering agent was incorporatedinto the foam disk of the buffer component 14 in accordance with thedetailed procedure set forth in Example 1. The pH buffering agent ofExamples 2, 4, and 5 was a mixture that contained about 50 weight %Amberlite® IRP-64 copolymer and about 50 weight % Amberlite® IRP-88copolymer. The carrier of the buffer suspension in Examples 2, 4, and 5was glycerine. The weight ratio of glycerine to resin in the buffersuspension was about 2.5 grams of glycerine per gram of the Amberlite®copolymer mixture.

The iontophoresis electrode 210 used in Example 3 was similar to theelectrode 210 used in Examples 2, 4, and 5, with the exception of thebuffer component 14. In the electrode 210 of Example 3, the buffercomponent 14 was a disk of polyester fleece that was coated with pHbuffering agent. The fleece disk had the same dimensions as the foamdisk that was used in the buffer component 14 of Examples 2, 4, and 5.The pH buffering agent included about 50 weight % Amberlite® IRP-64 andabout 50 weight % Amberlite® IRP-88. The coating of the pH bufferingagent included 0.35±0.05 grams of the Amberlite® copolymer mixture.

The coating of the Amberlite® copolymer mixture was placed as asubstantially uniform thickness onto one side of the polyester fleecedisk so that the Amberlite® copolymer mixture was sandwiched between theconductive component 16 and the polyester fleece disk. The coating wasprepared by mixing about 150 grams of the Amberlite® copolymer mixturewith about one liter of deionized water to make an aqueous slurry of theAmberlite® copolymer mixture. The polyester fleece disk was placed on anopen wire conveyor and passed under a flowing stream of the aqueousslurry of Amberlite® copolymers so that the aqueous slurry accumulatedas the buffer coating on one side of the disk to a thickness of about0.03 cm. The buffer-coated polyester fleece disk was then placed in anoven at a temperature of about 100° C. to evaporate the water containedin the coating. The buffer-coated polyester fleece disk was allowed todry in the oven until the weight of the buffer-coated polyester fleecedisk remained steady.

The iontophoresis electrode used in Comparative Example 1 included eachof the elements of the electrode 210 used in Examples 2, 4, and 5.However, in the electrode 210 of Comparative Example 1, the positions ofthe component 12 and the component 14 were switched so that thecomponent 12 was located between the conductive element 16 and thecomponent 14. The purpose of switching the components 12 and 14 inComparative Example 1 was to demonstrate that positioning of the pHbuffering agent with respect to the medicament delivery component 12 iscritical to attaining the surprising benefits of the present invention.

The iontophoresis electrode used in Comparative Example 2 was similar tothe electrode used in Example 3, with a couple of significantexceptions. First, the electrode of Comparative Example 2 did notinclude the component 12. Instead, the component 12 was deleted so thatthe component 14 was directly located between and in direct contact withthe conductive component 16 and the wicking layer 212. Second, thepolyurethane foam disk of the component 14 used in Comparative Example 2was made of the Rynel AMREL™ 6 polyurethane foam that was used to formthe medicament delivery component 12 in Examples 2, 4, and 5, ratherthan polyester fleece that was used to form the buffer component 14 inExample 3.

In Comparative 2, pH buffering agent was coated onto the foam disk ofthe buffer component 14 using the same procedure described in Example 3,with the exception that the buffer coating was a solution of pHbuffering agent and glycerine, rather than the solution of pH bufferingagent and water. The pH buffering agent that was coated onto the foamdisk of the component 14 in Comparative Example 2 consisted of the sameratio of Amberlite® copolymers and the same weight of Amberlite®copolymer mixture as the electrode 210 used in Example 3. The Amberlite®copolymer mixture and the glycerin were mixed in a ratio ofapproximately 1 gram of Amberlite® copolymer mixture to 2.5 grams ofglycerin. Other than for substitution of glycerin in place of water, thepH buffering agent that was coated onto the foam disk of the component14 in Comparative Example 2 was applied to the foam disk in accordancewith the details and procedure described in Example 3.

The iontophoresis electrode used in Comparative Example 3 was similar tothe iontophoresis electrode 210 used in Examples 2, 4, and 5, exceptthat the component 12 was deleted from the electrode used in ComparativeExample 3. The wicking layer 212 held the component 14 in place betweenthe wicking layer 212 and the conductive component 16 in ComparativeExample 3. The polyurethane foam disk of the component 14 used in thisExample was made of the Foamex PREMIUM polyurethane foam that was usedto form the buffer component 14 in Examples 2, 4, and 5. The poredensity and average pore diameter of the Foamex PREMIUM polyurethanefoam used in Comparative Example 3 was the same as that of the FoamexPREMIUM polyurethane foam used in Examples 2, 4, and 5. The foam disk ofthe component 14 in Comparative Example 3 had the same dimensions as thecomponent 14 foam disk in Examples 2, 4, and 5.

The component 14 of the electrode used in Comparative Example 3incorporated the same ratio of Amberlite® copolymers and the same weightof Amberlite® copolymer mixture as the electrode 210 used in Examples 2,4, and 5. The pH buffering agent was incorporated into the foam disk ofthe component 14 in accordance with the details and procedure describedin Examples 1, 2, 4, and 5.

The iontophoresis electrode used in Comparative Examples 4, 5, and 6included the conductive component 16, conductive terminal 18, andadhesive covering 20, as arranged in the electrode 210. The electrode ofComparative Examples 4, 5, and 6 also included the buffer component 14of the electrode 210, though the disk of absorbent material of thecomponent 14 in these Comparative Examples was made of the polyesterfleece that was used to form the buffer component 14 in Example 3,rather than the Foamex PREMIUM polyurethane foam that was used to formthe buffer component 14 in Examples 2, 4, and 5. The dimensions of thepolyester disk that was used in forming the component 14 were the samein Comparative Examples 4, 5, and 6 as in Example 3. The wicking layer212 held the component 14 in place between the wicking layer 212 and theconductive component 16. The component 12 was not included in theelectrode of Comparative Examples 4, 5, and 6.

Another difference in Comparative Examples 4, 5, and 6 was that the pHbuffering agent was applied as a coating to the surface of the component14 polyester disk that faced the conductive component 16. The pHbuffering agent included about 50 weight % Amberlite® IRP-64 and about50 weight % Amberlite® IRP-88. The coating of the pH buffering agentincluded 0.35±0.05 grams of the Amberlite® copolymer mixture. Thecoating of the Amberlite® copolymer mixture was placed as asubstantially uniform thickness onto one side of the polyester disk sothat the Amberlite® copolymer mixture was sandwiched between theconductive component 16 and the polyester disk.

The coating was prepared by mixing about 150 grams of the Amberlite®copolymer mixture with about one liter of deionized water to make anaqueous slurry of the Amberlite® copolymer mixture. The polyester diskwas placed on an open wire conveyor and passed under a flowing stream ofthe aqueous slurry of Amberlite® copolymers so that the aqueous slurryaccumulated on one side of the disk to a thickness of about 0.03 cm. Thebuffer-coated disk was then placed in an oven at a temperature of about100° C. to evaporate the water contained in the coating. Thebuffer-coated disk was allowed to dry in the oven until the weight ofthe disk remained steady.

EXAMPLES 2-3 AND COMPARATIVE EXAMPLES 1-4

In these Examples and Comparative Examples, a solution with a pH ofabout 5 to about 7 of 0.4 weight % dexamethasone sodium phosphate indeionized water was prepared. The dexamethasone sodium phosphatesolution contained a mixture of mono and di-valent anions that wereformed by dissociation of dexamethasone sodium phosphate within asolution pH range of about 5 to about 7. The dexamethasone sodiumphosphate solution was injected into the component 12, where theelectrode of the particular Example or Comparative Example included thecomponent 12, or into the component 14 where the electrode of theparticular Example or Comparative Example did not include the component12. Where the Example or Comparative Example included both the component12 and the component 14, it is believed that the dexamethasone sodiumphosphate solution was absorbed substantially uniformly into both thecomponent 12 and the component 14. The amount of the dexamethasonesodium phosphate solution that was injected into the various electrodesof Examples 2-3 and Comparative Examples 1-4 varied between 2 cc and 4cc, as seen in Table 4 below.

The electrode of the particular Example or Comparative Example waspositioned in the cell 710 with the wicking layer 212 disposed againstthe mouse skin 726. The system 710 was then permitted to operate for aperiod of 40 minutes with a current of 4 amps in the negative polaritymode applied to the conductor 722. Since the effective delivery area ofeach electrode used in Examples 2-3 and Comparative Examples 1-4,proximate the mouse skin 726, was about 22 cm², the current density foreach replicate of each of these Examples and Comparative Examples wasabout 0.18 mA/cm², as indicated in Table 4. At least 10 experimentalreplicates were conducted for each Example and Comparative Example, ascan be seen in Table 4.

In FIG. 12, the cumulative amount of dexamethasone phosphate collectedin the receptor compartment 712, as determined by HPLC, is plottedagainst the applied charge for Examples 2-3 and Comparative Examples1-4. The mean amount of dexamethasone phosphate that accumulated in thereceptor compartment 712 after a period of 40 minutes is numericallypresented in Table 4 and is graphically visible in FIG. 12 for Examples2-3 and Comparative Examples 1-4.

                                      TABLE 4    __________________________________________________________________________                                   Comparative                                           Comparative                                                   Comparative                                                           Comparative                   Example 2                           Example 3                                   Example 1                                           Example 2                                                   Example 3                                                           Example    __________________________________________________________________________                                                           4    Aqueous Medicament Solution                   4 cc of 0.4% wt.                           4 cc of 0.4% wt.                                   4 cc of 0.4% wt.                                           3 cc of 0.4% wt.                                                   2 cc of 0.4%                                                           3 cc of 0.4% wt.                   Dexamethasone                           Dexamethasone                                   Dexamethasone                                           Dexamethasone                                                   Dexamethasone                                                           Dexamethasone                   Sodium  Sodium  Sodium  Sodium  Sodium  Sodium                   Phosphate                           Phosphate                                   Phosphate                                           Phosphate                                                   Phosphate                                                           Phosphate    Time of operation, min                   40      40      40      40      40      40    Current (I), mA                   4       4       4       4       4       4    Polarity       Negative                           Negative                                   Negative                                           Negative                                                   Negative                                                           Negative    Effective Delivery Area (A), cm.sup.2                   22      22      22      22      22      22    Current Density (i), mA/cm.sup.2                   0.18    0.18    0.18    0.18    0.18    0.18    Mean amount of Medicament                   316.8 ± 108.0                           294.0 ± 114.0                                   21.3 ± 11.4                                           175.3 ± 65.4                                                   11.5 ± 5.8                                                           46 ± 16.9    Delivered    After 40 minutes, μg ± sd    Medicament Delivery Rate,                   2.36    2.35    0.17    1.32    0.08    0.33    μg/mA · min    Steady State Medicament Flux,                   25.7    25.7    1.8     14.4    0.84    3.6    μg/cm.sup.2 /hour    Number of Experimental                   40      10      15      15      30      40    Replicates    __________________________________________________________________________

The results in Table 4 and FIG. 12 demonstrate that the electrode 210 ofthe present invention, whether incorporating pH buffering agent withinthe component 14 or as the buffer coating of the component 14, deliveredabout 15 times more dexamethasone phosphate than the electrode ofComparative Example 1, where the positions of the components 12 and 14were reversed. These results also demonstrate that the inventiveelectrode 210 delivered about 6 times more dexamethasone phosphate thanthe single fleece layer electrode of Comparative Example 4. Theseresults demonstrate that the electrode of Comparative Example 3, whichutilizes the same component 14 as the Example 2 electrode, but excludesthe component 12 of the Example 2 electrode, exhibited the poorestdelivery performance. This design of Comparative Example 3 deliveredabout 30 times less dexamethasone phosphate than the electrode 210 ofExamples 2 and 3.

The cumulative amount of dexamethasone phosphate delivered to thereceptor compartment 712, per unit of effective delivery area for theelectrodes of the particular Examples and Comparative Examples, areplotted in FIG. 13 as a function of time. The steady state flux ofdexamethasone phosphate from the donor compartment 714 into the receptorcompartment 712 was calculated as set forth above based on the slope ofthe linear portion of each plot of FIG. 13. The lag time fordexamethasone phosphate delivery into the receptor compartment 712 wasfound to be about 10 minutes for each of the electrodes of Examples 2-3and Comparative Examples 1-4.

The steady state fluxes of dexamethasone phosphate from the donorcompartment 714 into the receptor compartment 712 for Examples 2-3 andComparative Examples 1-4 are presented in Table 4. These results showthat the electrodes of Examples 2 and 3 each exhibited an identicalsteady state flux of 25.7 μg/cm² -hr for dexamethasone phosphate. Theseidentical values for steady state flux demonstrate that the buffercomponent 14 of the inventive electrode performs in the same superiorway, regardless of whether the pH buffering agent is applied to theabsorbent material of the buffer component as part of the buffercoating, or is alternatively incorporated into the absorbent material ofthe buffer component 14 as part of the buffer suspension. On the otherhand, the steady state flux of dexamethasone phosphate from theelectrode of Comparative Example 1 was only 1.8 μg/cm² -hr. This lowsteady state flux of Comparative Example 1, as compared to the highsteady state fluxes of Examples 2 and 3, further demonstrates howpositioning of the pH buffering agent with respect to the medicamentdelivery component 12 in accordance with the present invention iscritical to attaining the surprising benefits of the present invention.

EXAMPLE 4 AND COMPARATIVE EXAMPLE 5

In this Example and Comparative Example, a solution with a pH of fromabout 4.0 to 5.5 of 4.0 weight % lidocaine hydrochloride in deionizedwater was prepared. The lidocaine hydrochloride solution contained amixture of chloride ions and protonated lidocaine ions that were formedby dissociation of lidocaine hydrochloride in the solution. Thelidocaine hydrochloride solution was injected into the component 12 inExample 4 and into the component 14 in Comparative Example 5. It isbelieved that the lidocaine hydrochloride solution was absorbedsubstantially uniformly into both the component 12 and the component 14in Example 4. The amount of the lidocaine hydrochloride solution thatwas injected into the electrode of Example 4 was 4 cc, and the amount ofthe lidocaine hydrochloride solution that was injected into theelectrode of Comparative Example 5 was 3 cc, as seen in Table 5 below.

The electrodes of the Example and Comparative Example were positioned inthe cell 710 with the wicking layer 212 disposed against the mouse skin726. The system 710 was then permitted to operate for a period of 40minutes with a current of 4 amps in the positive polarity mode appliedto the conductor 722. Since the effective delivery area of theelectrodes used in Example 4 and Comparative Example 5, proximate themouse skin 726, was about 22 cm², the current density for each replicateof each Example and Comparative Example was about 0.18 mA/cm², asindicated in Table 5. At least 15 experimental replicates were conductedfor each Example and Comparative Example, as shown in Table 5.

                  TABLE 5    ______________________________________                   Comparative                   Example 5 Example 4    ______________________________________    Aqueous Medicament Solution                     3 cc of 4.0% wt.                                 4 cc of 4.0% wt.                     Lidocaine   Lidocaine                     Hydrochloride                                 Hydrochloride    Time of Operation, min                     40          40    Current (I), mA  4           4    Polarity         Positive    Positive    Effective Delivery Area (A), cm.sup.2                     22          22    Current Density (i), mA/cm.sup.2                     0.18        0.18    Mean amount of Medicament                     500.8 ± 139.1                                 1028.0 ± 202.4    Delivered After 40 minutes,    μg ± sd    Medicament Delivery Rate,                     3.7         7.2    μg/mA · min    Steady State Medicament Flux,                     40.4        79.0    μg/cm.sup.2 /hour    Number of Experimental                     15          25    Replicates    ______________________________________

The cumulative amount of protonated lidocaine collected in the receptorcompartment 712, as determined by HPLC, is plotted against the appliedcharge in FIG. 14 for Example 4 and Comparative Example 5. The meanamount of protonated lidocaine that accumulated in the receptorcompartment 712 after a period of 40 minutes is numerically presented inTable 5 and is graphically visible in FIG. 14 for Example 4 andComparative Example 5. These results in Table 5 and FIG. 14 demonstratethat the electrode 210 of the present invention delivered about 2 timesmore protonated lidocaine than the single fleece layer electrode ofComparative Example 5.

The cumulative amount of protonated lidocaine delivered to the receptorcompartment 712, per unit of effective delivery area of the electrodesof Example 4 and Comparative Example 5, are plotted in FIG. 15 as afunction of time. The steady state flux of protonated lidocaine from thedonor compartment 714 into the receptor compartment 712 was calculatedas set forth above based on the slope of the linear portion of each plotof FIG. 15. The lag time for protonated lidocaine delivery into thereceptor compartment 712 was found to be about 10 minutes for theelectrodes of Example 4 and Comparative Example 5.

The steady state fluxes of protonated lidocaine from the donorcompartment 714 into the receptor compartment 712 for Example 4 andComparative Example 5 are presented in Table 5. These resultsdemonstrate that the steady state flux of the protonated lidocaine fromthe electrode of Example 4 was 79.0 μg/cm² -hr, whereas the steady stateflux of the protonated lidocaine from the electrode of ComparativeExample 5 was only 40.4 μg/cm² -hr.

EXAMPLE 5 AND COMPARATIVE EXAMPLE 6

In this Example and Comparative Example, a solution of 0.5 weight %minoxidil tartrate in deionized water was prepared. The minoxidiltartrate solution contained a mixture of minoxidil ions and tartrateions that were formed by dissociation of minoxidil tartrate in thesolution. The minoxidil tartrate solution was injected into thecomponent 12 in Example 5 and into the component 14 in ComparativeExample 6. It is believed that the minoxidil tartrate solution wasabsorbed substantially uniformly into both the component 12 and thecomponent 14 in Example 5. The amount of the minoxidil tartrate solutionthat was injected into the electrode of Example 5 was 4 cc, and theamount of the minoxidil tartrate solution that was injected into theelectrode of Comparative Example 6 was 3 cc, as seen in Table 6 below.

The electrodes of the Example and Comparative Example were positioned inthe cell 710 with the wicking layer 212 disposed against the mouse skin726. The system 710 was then permitted to operate for a period of 40minutes with a current of 4 amps in the positive polarity mode appliedto the conductor 722. Since the effective delivery area of theelectrodes used in Example 5 and Comparative Example 6, proximate themouse skin 726, was about 22 cm², the current density for each replicateof each Example and Comparative Example was about 0.18 mA/cm², asindicated in Table 6. At least 15 experimental replicates were conductedfor each Example and Comparative Example, as shown in Table 6.

                  TABLE 6    ______________________________________                   Comparative                   Example 6 Example 5    ______________________________________    Aqueous Medicament Solution                     3 cc of 0.5% wt.                                 4 cc of 0.5% wt.                     Minoxidil   Minoxidil                     Tartrate    Tartrate    Time of operation (t), min                     40          5-30    Current (I), mA  4           4    Polarity         Positive    Positive    Effective Delivery Area, cm.sup.2                     22          22    Current Density (i), mA/cm.sup.2                     0.18        0.18    Mean amount of Medicament                     19.6 ± 7.5                                 99.7.6 ± 29.8    Delivered After 40 minutes,    μg ± sd    Medicament Delivery Rate,                     0.13        0.75    μg/mA · min    Steady State Medicament Flux,                     1.4         8.1    μg/cm.sup.2 /hour    Number of Experimental                     16          17    Replicates    ______________________________________

The cumulative amount of minoxidil ions collected in the receptorcompartment 712, as determined by HPLC, is plotted against the appliedcharge in FIG. 16 for Example 5 and Comparative Example 6. The meanamount of minoxidil ions that accumulated in the receptor compartment712 after a period of 40 minutes is numerically presented in Table 6 andis graphically visible in FIG. 16 for Example 5 and Comparative Example6. These results in Table 6 and FIG. 16 demonstrate that the electrode210 of the present invention delivered about five times more minoxidilions than the single foam layer electrode of Comparative Example 6.

The cumulative amount of minoxidil ion delivered to the receptorcompartment 712, per unit of effective delivery area of the electrodesof Example 5 and Comparative Example 6, are plotted in FIG. 17 as afunction of time. The steady state flux of minoxidil ions from the donorcompartment 714 into the receptor compartment 712 was calculated as setforth above based on the slope of the linear portion of each plot ofFIG. 17. The lag time for minoxidil ions delivery into the receptorcompartment 712 was found to be about 10 minutes for the electrodes ofExample 5 and Comparative Example 6.

The steady state fluxes of minoxidil ions from the donor compartment 714into the receptor compartment 712 for Example 5 and Comparative Example6 are presented in Table 6. These results demonstrate that the steadystate flux of the minoxidil ions from the electrode of Example 5 was 8.1μg/cm² -hr, whereas the steady state flux of the minoxidil ions from theelectrode of Comparative Example 6 was only 1.4 μg/cm² -hr.

Although the present invention has been described with reference topreferred embodiments, workers skilled in the art will recognize thatchanges may be made in form and detail without departing from the spiritand scope of the invention.

What is claimed is:
 1. A process for making a medical electrodecomponent, the process comprising:heterogeneously dispersing a pHbuffering agent within a first absorbent material to form a pH buffercomponent that is capable of absorbing electrolytic solution; forming afirst web from the first absorbent material, the first web having firstand second surfaces; forming a second web from a second absorbentmaterial that is capable of absorbing electrolytic solution; cuttingthrough the first web to form a first web portion having a first surfaceand a second surface; cutting through the second web to form a secondweb portion having a first surface and a second surface, the second webportion comprising a medicament delivery component; and securing thesecond surface of the first web portion and the first surface of thesecond web portion in contact to secure the first web portion and thesecond web portion in layered relation.
 2. The process of claim 1wherein dispersing the pH buffering agent within the first absorbentmaterial comprises:dispersing the pH buffering agent within the firstabsorbent material either before forming the first web, after formingthe first web and before forming the first web portion, or after formingthe first web portion.
 3. The process of claim 1, the process furthercomprising dispersing conductive particles within the first absorbentmaterial to make the first absorbent material electrically conductive.4. A process of making a medical electrode using the medical electrodecomponent made in accordance with claim 1, the process comprisingplacing an electrical connection in electrical communication with thefirst web portion.
 5. A medical electrode made by the process of claim4.
 6. The process of claim 1, the process further comprising:forming athird web; cutting through the third web to form a third web portionhaving a first surface and a second surface; and adhesively securing thesecond surface of the third web portion against the first surface of thefirst web portion with the first web portion disposed between the secondweb portion and the third web portion and with the second web portion inlayered relation with a majority of the first web portion and a majorityof the third web portion.
 7. The process of claim 1, the process furthercomprising:forming a third web from a conductive material; cuttingthrough the third web to form a third web portion having a first surfaceand a second surface; and securing the second surface of the third webportion and the first surface of the first web portion in contact tosecure the first web portion, the second web portion, and the third webportion in layered relation as the medical electrode component.
 8. Theprocess of claim 7, the process further comprising:forming a fourth web;cutting through the fourth web to form a fourth web portion having afirst surface and a second surface; and securing the second surface ofthe fourth web portion to the first surface of the third web portionwith the first web portion and the third web portion disposed betweenthe second web portion and the fourth web portion.
 9. The process ofclaim 1 wherein the pH buffering agent comprises ion-exchange resin. 10.The process of claim 1, the process further comprising:providing the pHbuffering agent with one or more different ion-exchange functionalgroups that are selected from the group consisting of a carboxyl group,an amino group, a --SO₃ H group, and an --OPO₃ H₂ group.
 11. The processof claim 1, the process further comprising:selecting the first absorbentmaterial and the second absorbent material from the group consisting ofa resinous material, a fibrous material, a colloidal material and amixture of any of these.
 12. The process of claim 11, the processfurther comprising:selecting the resinous material from the groupconsisting of polyurethane, polyvinylpyrrolidone, polyvinyl alcohol,polyethylene oxide, polyacrylic acid, polyethylene glycol,polyacrylamide, and a cellulose derivative; and selecting the fibrousmaterial from the group consisting of polyester, rayon, cotton, andwool.
 13. The process of claim 1, the process furthercomprising:locating the first web portion adjacent to and in contactwith the second web portion at a distinct interface between the firstweb portion and the second web portion; and selecting the firstabsorbent material and the second absorbent material so that thedistinct interface is capable of remaining intact during the entire lifeof the electrode component.
 14. The process of claim 13, the processfurther comprising:selecting the first absorbent material and the secondabsorbent material so that the distinct interface is capable ofpreventing the first absorbent material from merging with the secondabsorbent material during the entire life of the electrode.
 15. Theprocess of claim 1 wherein dispersing the pH buffering agent within thefirst absorbent material comprises:preparing a suspension of the pHbuffering agent and a carrier for the pH buffering agent.
 16. Theprocess of claim 15, the process further comprising:selecting thecarrier from the group consisting of glycerine, a solution of polyvinylalcohol, a solution of polyethylene glycol, a solution of polyethyleneoxide, a solution of peptide-based gelatin, a solution of a plant-basedgum, a dispersant, and a mixture of any of these.
 17. The process ofclaim 15 wherein dispersing the pH buffering agent within the firstabsorbent material further comprises applying the suspension to thefirst absorbent material to disperse the pH buffering agent within thefirst absorbent material.
 18. The process of claim 17 wherein the firstabsorbent layer is between about 2.5 millimeters and about 3 millimetersthick.
 19. The process of claim 17 wherein the first absorbent layer hasa thickness of at least about 2.5 millimeters.
 20. The process of claim15, the method further comprising placing electrolytic solution in themedicament delivery component, the pH buffering agent capable of holdingabout 0.1 milliequivalents of acid or about 0.1 milliequivalents of baseduring an iontophoresis period of about 40 minutes or more whilemaintaining the pH of the electrolytic solution within a range of about4 to about 8 standard pH units.
 21. The process of claim 15 wherein thefirst absorbent material comprises foam.
 22. The process of claim 15wherein:the suspension comprises at least a first phase and a secondphase, the first phase and the second phase physically separable fromeach other; the first phase comprises the pH buffering agent; and thesecond phase comprises the carrier.
 23. The process of claim 15 whereinthe pH buffering agent is insoluble in the carrier.
 24. The process ofclaim 15 wherein the pH buffering agent comprises ion exchange resin.25. The process of claim 1 wherein dispersing the pH buffering agentwithin the first absorbent material comprises:mixing the pH bufferingagent and one or more prepolymers of the first absorbent material;blowing the mixture to form heterogenous pH buffering foam; and settingthe foam.
 26. The process of claim 1 wherein dispersing the pH bufferingagent within the first absorbent material comprises:mixing the pHbuffering agent and water to form an aqueous suspension; and mixing oneor more prepolymers of the first absorbent material and the aqueoussuspension with agitation to form heterogenous pH buffering foam. 27.The process of claim 1 wherein dispersing the pH buffering agent withinthe first absorbent material comprises:melt blending the pH bufferingagent and particles of resinous material.
 28. The process of claim 1wherein the first absorbent material comprises foam.
 29. The process ofclaim 1 wherein:the pH buffer component comprises at least a first phaseand a second phase, the first phase and the second phase distinct fromeach other; the first phase comprises the pH buffering agent; and thesecond phase comprises the first absorbent material.
 30. The process ofclaim 1 wherein:the pH buffer component comprises at least a first phaseand a second phase, the first phase and the second phase chemicallyseparate from each other; the first phase comprises the pH bufferingagent; and the second phase comprises the first absorbent material. 31.The process of claim 1 wherein the first absorbent material is capableof absorbing at least about 500 milliliters of electrolytic solution persquare meter of first absorbent material surface area within about 5seconds or less and the second absorbent material is capable ofabsorbing at least about 500 milliliters of electrolytic solution persquare meter of second absorbent material surface area within about 5seconds or less.
 32. The process of claim 1 wherein the first absorbentmaterial is capable of absorbing at least about 2000 milliliters ofelectrolytic solution per square meter of first absorbent materialsurface area within about 5 seconds or less and the second absorbentmaterial is capable of absorbing at least about 2000 milliliters ofelectrolytic solution per square meter of second absorbent materialsurface area within about 5 seconds or less.
 33. The process of claim 1wherein the first absorbent material is capable of absorbing at leastabout 0.5 milliliters of electrolytic solution per gram of the firstabsorbent material within about 3 minutes or less and the secondabsorbent material is capable of absorbing at least about 0.5milliliters of electrolytic solution per gram of the second absorbentmaterial surface area within about 3 minutes or less.
 34. The process ofclaim 1 wherein the first absorbent material is capable of absorbing atleast about 1.0 milliliters of electrolytic solution per gram of thefirst absorbent material within about 3 minutes or less and the secondabsorbent material is capable of absorbing at least about 1.0milliliters of electrolytic solution per gram of the second absorbentmaterial surface area within about 3 minutes or less.
 35. A method ofusing the electrode component produced by the process of claim 1, themethod comprising:placing an electrical connection in working relationwith the second web to complete the electrode; and placing electrolyticsolution in the second web, the electrode capable of deliveringdexamethasone phosphate to a patient's body at a steady state flux of atleast about 26 μg/cm² /hour when a current of about -4 mA is applied tothe electrical connection, while maintaining the pH of the electrolyticsolution in the range of about 4 to about 8 standard pH units.
 36. Aprocess for making a medical electrode component, the processcomprising:applying a pH buffering agent as a coating on a substantiallyplanar surface of a first absorbent material; forming a first web fromthe first absorbent material, the first web having first and secondsurfaces; forming a second web from a second absorbent material that iscapable of absorbing electrolytic solution; cutting through the firstweb to form a first web portion having a first surface and a secondsurface; cutting through the second web to form a second web portionhaving a first surface and a second surface; and securing the secondsurface of the first web portion and the first surface of the second webportion in contact to secure the first web portion and the second webportion in layered relation, the pH buffering agent separated from thesecond web portion by the first absorbent material.
 37. The process ofclaim 36 wherein applying the pH buffering agent as a coating on asurface of the first absorbent material comprises:applying the coatingonto the first surface of either the first web or the first web portion.38. The process of claim 36 wherein coating the pH buffering agent onthe first absorbent material comprises:mixing the pH buffering agent andwater to form a slurry; applying the slurry to the substantially planarsurface of the first absorbent material to form a buffer coating on thefirst absorbent material.
 39. The process of claim 36 wherein the pHbuffering agent comprises ion exchange resin.
 40. The process of claim36, the process further comprising providing the pH buffering agent withone or more different ion-exchange functional groups that are selectedfrom the group consisting of a carboxyl group, an amino group, a --SO₃ Hgroup, and an --OPO₃ H₂ group.
 41. The process of claim 36, the processfurther comprising selecting the first absorbent material and the secondabsorbent material from the group consisting of a resinous material, afibrous material, a colloidal material, and a mixture of any of these.42. The process of claim 41, the process further comprising:selectingthe resinous material from the group consisting of polyurethane,polyvinylpyrrolidone, polyvinyl alcohol, polyethylene oxide, polyacrylicacid, polyethylene glycol, polyacrylamide, and a cellulose derivative;and selecting the fibrous material from the group consisting ofpolyester, rayon, cotton, and wool.
 43. The process of claim 36, theprocess further comprising:locating the first web portion adjacent toand in contact with the second web portion at a distinct interfacebetween the first web portion and the second web portion; and selectingthe first absorbent material and the second absorbent material so thatthe distinct interface is capable of remaining intact during the entirelife of the electrode component.
 44. The process of claim 43, theprocess further comprising:selecting the first absorbent material andthe second absorbent material so that the distinct interface is capableof preventing the first absorbent material from merging with the secondabsorbent material during the entire life of the electrode component.45. The process of claim 36 wherein coating the pH buffering agent onthe first absorbent material comprises:mixing the pH buffering agent andwater to form a slurry; applying the slurry to a substantially planarsurface of the first absorbent material to form a buffer coating on thefirst absorbent material.
 46. A method of using the electrode componentproduced by the process of claim 36, the method comprising:placing anelectrical connection in working relation with the second web to form anelectrode; and placing electrolytic solution in the second web, theelectrode capable of delivering dexamethasone phosphate to a patient'sbody at a steady state flux of at least about 26 μg/cm² /hour when acurrent of about -4 mA is applied to the electrical connection, whilemaintaining the pH of the electrolytic solution in the range of about 4to about 8 standard pH units.